Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors

ABSTRACT

Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

RELATED CASE

This application is a CON of Ser. No. 10/097,642, filed Mar. 15, 2002,now U.S. Pat. No. 6,683,210; which is a CON of Ser. No. 09/694,783,filed Oct. 24, 2000, now U.S. Pat. No. 6,388,132; which is a CON of Ser.No. 09/495,334, filed Feb. 1, 2000, now U.S. Pat. No. 6,316,496; whichis a CON of Ser. No. 08/913,096, filed Jan. 21, 1998, now U.S. Pat. No.6,143,788; which is a CON of Ser. No. 08/479,071, filed Jun. 7, 1995,now U.S. Pat. No. 6,150,556; which is a CIP of Ser. No. 08/402,450,filed Mar. 10, 1995, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds, composition and methodfor inhibiting retroviral proteases, such as human immunodeficiencyvirus (HIV) protease. This invention, in particular, relates tobis-amino acid hydroxyethylamine sulfonamide protease inhibitorcompounds, composition and method for inhibiting retroviral proteases,prophylactically preventing retroviral infection or the spread of aretrovirus, and treatment of a retroviral infection, e.g., an HIVinfection. The subject invention also relates to processes for makingsuch compounds as well as to intermediates useful in such processes.

During the replication cycle or gene transcription products aretranslated as proteins. These proteins are subsequently processed by avirally encoded protease (or proteinase) to yield viral enzymes andstructural proteins of the virus core. Most commonly, the gag precursorproteins are processed into the core proteins and the pol precursorproteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease active site that processing of the gag precursorprotein is prevented. Thus, attempts have been made to inhibit viralreplication by inhibiting the action of retroviral proteases.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitspecific processing of structural proteins and the release of retroviralprotease itself. In this manner, retroviral replication proteases can beeffectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors, ”Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990). U.S. Pat. No. 5,157,041, WO 94/04491, WO94/04492, WO 94/04493, WO 94/05639, WO 92/08701 and U.S. patentapplication Ser. No. 08/294,468, filed Aug. 23, 1994, (each of which isincorporated herein by reference in its entirety) for example describehydroxyethylamine, hydroxyethylurea or hydroxyethyl sulfonamide isosterecontaining retroviral protease inhibitors.

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. EP 468 641 discloses renininhibitors and intermediates for the preparation of the inhibitors whichinclude sulfonamide-containing hydroxyethylamine compounds, such as3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol.G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylaminerenin inhibitors, and EP 0264 795 discloses certainsulfonamide-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally are not predictive for effective HIV protease inhibition.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to selected retroviral protease inhibitorcompounds, analogs and pharmaceutically acceptable salts, esters andprodrugs thereof. The subject compounds are characterized as bis-aminoacid hydroxyethylamine sulfonamide inhibitor compounds. The inventioncompounds advantageously inhibit retroviral proteases, such as humanimmunodeficiency virus (HIV) protease. Therefore, this invention alsoencompasses pharmaceutical compositions, methods for inhibitingretroviral proteases and methods for treatment or prophylaxis of aretroviral infection, such as an HIV infection. The subject inventionalso relates to processes for making such compounds as well as tointermediates useful in such processes.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein

-   R¹ represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,    cyanoalkyl, imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂S(O)₂NH₂,    —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃    or —C(CH₃)₂S(O)₂CH₃ radicals; preferably, R¹ represents alkyl of 1-5    carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon    atoms, hydroxyalkyl of 1-3 carbon atoms, alkoxyalkyl of 1-3 alkyl    and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3 alkyl carbon atoms,    imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂S(O)₂NH₂, —CH₂SCH₃,    —CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃ or    —C(CH₃)₂S(O)₂CH₃ radicals; more preferably, R¹ represents alkyl of    1-4 carbon atoms, alkenyl of 2-3 carbon atoms, alkynyl of 3-4 carbon    atoms, cyanomethyl, imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂,    —CH₂S(O)₂NH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃,    —C(CH₃)₂S(O)CH₃ or —C(CH₃)₂S(O)₂CH₃ radicals; and most preferably,    R¹ represents sec-butyl, tert-butyl, iso-propyl, 3-propynyl,    cyanomethyl or —C(CH₃)₂S(O)₂CH₃ radicals;-   R² represents alkyl, aralkyl, alkylthioalkyl, arylthioalkyl or    cycloalkylalkyl radicals; preferably, R² represents radicals of    alkyl of 1-5 carbon atoms, aralkyl of 1-3 alkyl carbon atoms,    alkylthioalkyl of 1-3 alkyl carbon atoms, arylthioalkyl of 1-3 alkyl    carbon atoms or cycloalkylalkyl of 1-3 alkyl carbon atoms and 3-6    ring member carbon atoms; more preferably, R² represents radicals of    alkyl of 3-5 carbon atoms, arylmethyl, alkylthioalkyl of 1-3 alkyl    carbon atoms, arylthiomethyl or cycloalkylmethyl of 5-6 ring member    carbon atoms radicals; even more preferably; R² represents isobutyl,    n-butyl, CH₃SCH₂CH₂—, benzyl, phenylthiomethyl,    (2-naphthylthio)methyl, 4-methoxyphenylmethyl,    4-hydroxyphenylmethyl, 4-fluorophenylmethyl or cyclohexylmethyl    radicals; even more preferably, R² represents benzyl,    4-fluorophenylmethyl or cyclohexylmethyl radicals; most preferably,    R² represents benzyl;-   R³ represents alkyl, cycloalkyl or cycloalkylalkyl radicals;    preferably, R³ represents radicals of alkyl radical of 1-5 carbon    atoms, cycloalkyl of 5-8 ring members or cycloalkylmethyl radical of    3-6 ring members; more preferably, R³ represents propyl, isoamyl,    isobutyl, butyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl or    cycloheptyl radicals; more preferably R³ represents isobutyl or    cyclopentylmethyl radicals;-   R⁴ represents aryl, heteroaryl or heterocyclo radicals provided R¹¹    is other than a hydrogen radical and R⁴ represents heterocyclo or    benzo fused heteroaryl radicals provided R¹¹ is a hydrogen radical;    preferably, R⁴ represents aryl, benzo fused 5 to 6 ring member    heteroaryl or benzo fused 5 to 6 ring member heterocyclo radicals    provided R¹¹ is other than a hydrogen radical and R⁴ represents    benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring    member heterocyclo radicals provided R¹¹ is a hydrogen radical; or-   R⁴ represents a radical of the formula-    wherein A and B each independently represent O, S, SO or SO₂;    preferably, A and B each represent O;-   R⁶ represents deuterium, alkyl or halogen radicals; preferably, R⁶    represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro    radicals; more preferably R⁶ represents deuterium, methyl, ethyl,    propyl, isopropyl or fluoro radicals;-   R⁷ represents hydrogen, deuterium, alkyl or halogen radicals;    preferably, R⁷ represents hydrogen, deuterium, alkyl of 1-3 carbon    atoms, fluoro or chloro radicals; more preferably, R⁷ represents    hydrogen, deuterium, methyl or fluoro radicals; or R⁶ and R⁷ each    independently represent fluoro or chloro radicals; and preferably,    R⁶ and R⁷ each represent a fluoro radical; or-   R⁴ represents a radical of the formula-    wherein Z represents O, S or NH; and R⁹ represents a radical of    formula-    wherein Y represents O, S or NH; X represents a bond, O or NR²¹;-   R²⁰ represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl,    heteroaralkyl, heterocycloalkyl, aminoalkyl, N-mono-substituted or    N,N-disubstituted aminoalkyl wherein said substituents are alkyl or    aralkyl radicals, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl or    hydroxyalkyl radicals; preferably, R²⁰ represents hydrogen, alkyl of    1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to    5 carbon atoms, aralkyl of 1 to 5 alkyl carbon atoms, heteroaralkyl    of 5 to 6 ring members and 1 to 5 alkyl carbon atoms,    heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkyl carbon    atoms, aminoalkyl of 2 to 5 carbon atoms, N-mono-substituted or    N,N-disubstituted aminoalkyl of 2 to 5 alkyl carbon atoms wherein    said substituents are radicals of alkyl of 1 to 3 carbon atoms,    aralkyl of 1 to 3 alkyl carbon atoms radicals, carboxyalkyl of 1 to    5 carbon atoms, alkoxycarbonylalkyl of 1 to 5 alkyl carbon atoms,    cyanoalkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to 5 carbon    atoms; more preferably, R²⁰ represents hydrogen, alkyl of 1 to 5    carbon atoms, phenylalkyl of 1 to 3 alkyl carbon atoms,    heterocycloalkyl of 5 to 6 ring members and 1 to 3 alkyl carbon    atoms, or N-mono-substituted or N,N-disubstituted aminoalkyl of 2 to    3 carbon atoms wherein said substituents are alkyl radicals of 1 to    3 carbon atoms; and most preferably, R²⁰ represents hydrogen,    methyl, ethyl, propyl, isopropyl, isobutyl, benzyl,    2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl,    2-(1-piperazinyl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl,    2-(1-morpholinyl)ethyl, 2-(1-thiamorpholinyl)ethyl or    2-(N,N-dimethylamino)ethyl radicals;-   R²¹ represents hydrogen or alkyl radicals; preferably, R²¹    represents hydrogen radical or alkyl radical of 1 to 3 carbon atoms;    more preferably, R²¹ represents hydrogen or methyl radicals; and    most preferably, R²¹ represents a hydrogen radical; or-   the radical of formula —NR²⁰R²¹ represents a heterocyclo radical;    preferably, the radical of formula —NR²⁰R²¹ represents a 5 to 6 ring    member heterocyclo radical; more preferably, the radical of formula    —NR²⁰R²¹ represents pyrrolidinyl, piperidinyl, piperazinyl,    4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl or    thiamorpholinyl radicals; and-   R²² represents alkyl or R²⁰R²¹N-alkyl radicals; preferably, R²²    represents alkyl or R²⁰R²¹N-alkyl radicals wherein alkyl is 1 to 3    carbon atoms; and more preferably, R²² represents alkyl radical of 1    to 3 carbon atoms; and-   preferably R⁴ represents phenyl, 2-naphthyl, 4-methoxyphenyl,    4-hydroxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl or 4-aminophenyl    radicals provided R¹¹ is other than a hydrogen radical, or R⁴    represents benzothiazol-5-yl, benzothiazol-6-yl,    2-amino-benzothiazol-5-yl,    2-(methoxycarbonylamino)benzothiazol-5-yl,    2-amino-benzothiazol-6-yl, 2-(methoxycarbonylamino)    benzothiazol-6-yl, 5-benzoxazolyl, 6-benzoxazolyl, 6-benzopyranyl,    3,4-dihydrobenzopyran-6-yl, 7-benzopyranyl,    3,4-dihydrobenzopyran-7-yl, 2,3-dihydrobenzofuran-5-yl,    benzofuran-5-yl, 1,3-benzodioxol-5-yl,    2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,    2,2-dideutero-1,3-benzodioxol-5-yl,    2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,    5-benzimidazolyl, 2-(methoxycarbonylamino)benzimidazol-5-yl,    6-quinolinyl, 7-quinolinyl, 6-isoquinolinyl or 7-isoquinolinyl    radicals; more preferably, R⁴ represents phenyl, 2-naphthyl,    4-methoxyphenyl or 4-hydroxyphenyl radicals provided R¹¹ is other    than a hydrogen radical, or R⁴ represents benzothiazol-5-yl,    benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl,    benzofuran-5-yl, 1,3-benzodioxol-5-yl,    2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,    2,2-dideutero-1,3-benzodioxol-5-yl,    2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,    2-(methoxycarbonylamino)benzothiazol-5-yl,    2-(methoxycarbonylamino)benzothiazol-6-yl or    2-(methoxycarbonylamino)benzimidazol-5-yl radicals; and most    preferably, R⁴ represents phenyl, 4-methoxyphenyl or 4-hydroxyphenyl    radicals provided R¹¹ is other than a hydrogen radical, or R⁴    represents benzothiazol-5-yl, benzothiazol-6-yl,    2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl,    2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,    2,2-dideutero-1,3-benzodioxol-5-yl,    2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,    2-(methoxycarbonylamino)benzothiazol-6-yl or    2-(methoxycarbonylamino)benzimidazol-5-yl radicals;-   R¹⁰ represents hydrogen, alkyl, hydroxyalkyl or alkoxyalkyl    radicals; preferably, R¹⁰ represents hydrogen, alkyl, hydroxyalkyl    or alkoxyalkyl radicals, wherein alkyl and alkoxy are each 1-3    carbon atoms; more preferably, R¹⁰ represents hydrogen, methyl,    ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl or    methoxyethyl radicals: most preferably, R¹⁰ represents hydrogen,    methyl or ethyl radicals;-   R¹¹ represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aralkyl,    heteroaralkyl, alkylthioalkyl or the sulfone or sulfoxide    derivatives thereof, —CH₂CH₂CONH₂ or —CH₂CONH₂ radicals; preferably,    R¹¹ represents hydrogen, alkyl of 1-5 carbon atoms, hydroxyalkyl of    1-4 carbon atoms, alkoxyalkyl of 1-4 alkyl carbon atoms, benzyl,    imidazolylmethyl, —CH₂CH₂CONH₂, —CH₂CONH₂, —CH₂CH₂SCH₃ or —CH₂SCH₃    radicals or the sulfone or sulfoxide derivatives thereof; more    preferably, R¹¹ represents hydrogen, methyl, ethyl, propyl,    isopropyl, butyl, secbutyl, isobutyl, tertbutyl, hydroxymethyl,    hydroxyethyl, methoxymethyl or methoxyethyl radicals; most    preferably, R¹¹ represents hydrogen, methyl or ethyl radicals; and-   R¹² and R¹³ each independently represent hydrogen, alkyl, aralkyl,    heteroaralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,    alkoxyalkyl, aryl or heteroaryl radicals; preferably, R¹² and R¹³    each independently represent hydrogen, alkyl, aralkyl,    heteroaralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,    alkoxyalkyl, aryl or heteroaryl radicals, wherein alkyl is 1-5    carbon atoms, cycloalkyl is 3-6 ring member cycloalkyl optionally    benzo fused, and heteroaryl is 5 to 6 ring member heteroaryl    optionally benzo fused; more preferably, R¹² and R¹³ each    independently represent hydrogen, alkyl of 1-5 carbon atoms,    phenylalkyl of 1-3 alkyl carbon atoms, 5 to 6 ring member    heteroaralkyl of 1-3 alkyl carbon atoms, cycloalkyl of 3-6 ring    members, cycloalkylmethyl of 3-6 ring members, hydroxyalkyl of 1-3    carbon atoms, methoxyalkyl of 1-3 alkyl carbon atoms or phenyl    radicals; even more preferably, R¹² and R¹³ each independently    represent hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, benzyl,    phenylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,    2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl,    furylmethyl, 2-furylethyl, 2-hydroxyethyl, 2-methoxyethyl or phenyl    radicals; most preferably, R¹² represents hydrogen or methyl    radicals; and most preferably, R¹³ represents hydrogen, methyl,    ethyl, propyl, cyclopropyl, isopropyl, benzyl, 2-phenylethyl,    2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,    2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl,    furylmethyl, 2-furylethyl or 2-methoxyethyl radicals.

Another family of compounds of interest within Formula I as definedabove wherein R⁴ represents aryl, heteroaryl or heterocyclo radicalsprovided R¹ is other than hydrogen or alkyl radicals, and R⁴ representsheterocyclo or benzo fused heteroaryl radicals provided R¹¹ is ahydrogen or alkyl radical; preferably, R⁴ represents aryl, benzo fused 5to 6 ring member heteroaryl or benzo fused 5 to 6 ring memberheterocyclo radicals provided R¹¹ is other than hydrogen or alkylradicals, and R⁴ represents benzo fused 5 to 6 ring member heteroaryl orbenzo fused 5 to 6 ring member heterocyclo radicals provided R¹¹ is ahydrogen or alkyl radical.

The absolute stereochemistry of the carbon atom of —CH(OH)— group ispreferably (R). The absolute stereochemistry of the carbon atom of—CH(R¹)— group is preferably (S). The absolute stereochemistry of thecarbon atom of —CH(R²)— groups is preferably (S).

A family of compounds of particular interest within Formula I arecompounds embraced by the formula

or a pharmaceutically acceptable salt, prodrug or ester thereof, whereinn, R¹, R², R³, R⁴, R¹⁰, R¹¹, and R¹³ are as defined above.

A family of compounds of further interest within Formula II arecompounds embraced by the formula

or a pharmaceutically acceptable salt, prodrug or ester thereof, whereinR¹, R², R³, R⁴, R¹⁰, Rh, and R¹³ are as defined above.

A more preferred family of compounds within Formula III consists ofcompounds or a pharmaceutically acceptable salt, prodrug or esterthereof, wherein

-   R¹ represents sec-butyl, tert-butyl, iso-propyl, 3-propynyl,    cyanomethyl or —C(CH₃)₂S(O)₂CH₃ radicals;-   R² represents a benzyl radical;-   R³ represents propyl, isoamyl, isobutyl, butyl, cyclohexyl,    cycloheptyl, cyclopentylmethyl or cyclohexylmethyl radicals; and-   R⁴ is as defined above;-   R¹⁰ represents hydrogen, methyl, ethyl, propyl, hydroxymethyl or    hydroxyethyl radicals;-   R¹¹ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl,    secbutyl, isobutyl, tertbutyl, hydroxymethyl, hydroxyethyl,    methoxymethyl or methoxyethyl radicals; and-   R¹³ represents hydrogen, methyl, ethyl, propyl, isopropyl,    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,    benzyl, phenylethyl, 2-pyridylmethyl, 3-pyridylmethyl,    4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl,    2-(4-pyridyl)ethyl, furylmethyl, 2-furylethyl, 2-hydroxyethyl,    2-methoxyethyl or phenyl radicals.

Compounds of interest include the following:

-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-([(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl    amino)-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-([(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzofuran-5-yl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)    propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methyl    propyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methyl    propyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methyl    propyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methyl    propyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-methyl-1,3-benzodioxol-5-yl)sulfonyl](2-methyl    propyl)amino)-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino)-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-([(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,2-difluoro-1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-cyanopropanamide;-   2S-[[(N,N-dimethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[(N,N-dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-pentynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl)(2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino)-1S-(phenylmethyl)propyl)-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl)amino)-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl)-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl]-3S-methyl-pentanamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-benzylamino)acetyl]amino]-N-[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-12R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl)-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl)-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl)-3,3-dimethyl-butanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]N-[2R-hydroxy-3-[[benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-([(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino)-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl]2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino)-N-[2R-hydroxy-3-[[(2-naphthyl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl)(2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]-3-methyl-butanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl)-3S-methyl-pentanamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino)-N-[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)    propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino)-N-12R-hydroxy-3-[[benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-([(N-2-methoxyethylamino)acetyl]amino]-N-(2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[2-naphthyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide;-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl)(2-methylpropyl)    amino]-1S-(phenylmethyl)propyl]pent-4-ynamide; and-   2S-[[(N-2-methoxyethylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing preferablyfrom 1 to 8 carbon atoms, more preferably from 1 to 5 carbon atoms, mostpreferably 1 to 3 carbon atoms. Examples of such radicals includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term“hydroxyalkyl”, alone or in combination, means a alkyl radical asdefined above wherein at least one hydrogen atom has been replaced by ahydroxyl group, but no more than one hydrogen atom per carbon atom;preferably, 1 to 4 hydrogen atoms have been replaced by hydroxyl groups;more preferably, 1 to 2 hydrogen atoms have been replaced by hydroxylgroups; and most preferably, one hydrogen atom has been replaced by ahydroxyl group. The term “alkenyl”, alone or in combination, means astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing preferably from 2 to 10 carbon atoms, morepreferably from 2 to 8 carbon atoms, most preferably from 2 to 5 carbonatoms. Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. The term “alkynyl”, aloneor in combination, means a straight-chain or branched chain hydrocarbonradical having one or more triple bonds and containing preferably from 2to 10 carbon atoms, more preferably from 2 to 5 carbon atoms. Examplesof alkynyl radicals include ethynyl, propynyl (propargyl), butynyl andthe like. The term “alkoxyl”, alone or in combination, means an alkylether radical wherein the term alkyl is as defined above. Examples ofsuitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.The term “alkoxyalkyl”, alone or in combination, means a alkyl radicalas defined above wherein at least one hydrogen atom has been replaced bya alkoxy group, but no more than one hydrogen atom per carbon atom;preferably, 1 to 4 hydrogen atoms have been replaced by alkoxy groups;more preferably, 1 to 2 hydrogen atoms have been replaced by alkoxygroups; and most preferably, one hydrogen atom has been replaced by aalkoxy group. The term “cycloalkyl”, alone or in combination, means asaturated or partially saturated monocyclic, bicyclic or tricyclic alkylradical wherein each cyclic moiety contains preferably from 3 to 8carbon atom ring members, more preferably from 3 to 7 carbon atom ringmembers, most preferably from 5 to 6 carbon atom ring members, and whichmay optionally be a benzo fused ring system which is optionallysubstituted as defined herein with respect to the definition of aryl.Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl,2,3-dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and“tricyclic” as used herein are intended to include both fused ringsystems, such as naphthyl and β-carbolinyl, and substituted ringsystems, such as biphenyl, phenylpyridyl, naphthyl anddiphenylpiperazinyl. The term “cycloalkylalkyl” means an alkyl radicalas defined above which is substituted by a cycloalkyl radical as definedabove. Examples of such cycloalkylalkyl radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like. The term “benzo”, aloneor in combination, means the divalent radical C₆H₄=derived from benzene.The term “aryl”, alone or in combination, means a phenyl or naphthylradical which is optionally substituted with one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano,haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino,alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido,aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and thelike. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 4-CF₃-phenyl,3-acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl,2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and thelike. The terms “aralkyl” and “aralkoxy”, alone or in combination, meansan alkyl or alkoxy radical as defined above in which at least onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl,methylphenylmethyl, diphenylmethyl, diphenylmethoxy,4-methoxyphenylmethoxy and the like. The term “aralkoxycarbonyl”, aloneor in combination, means a radical of the formula aralkyl-O—C(O)— inwhich the term “aralkyl” has the significance given above. Examples ofan aralkoxycarbonyl radical are benzyloxycarbonyl and4-methoxyphenylmethoxycarbonyl. The term “aryloxy” means a radical ofthe formula aryl-O— in which the term aryl has the significance givenabove. The term “alkanoyl”, alone or in combination, means an acylradical derived from an alkanecarboxylic acid, examples of which includeacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. Theterm “cycloalkylcarbonyl” means an acyl radical of the formulacycloalkyl-C(O)— in which the term “cycloalkyl” has the significancegive above, such as cyclopropylcarbonyl, cyclohexylcarbonyl,adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like. The term“aralkanoyl” means an acyl radical derived from an aryl-substitutedalkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term “aroyl” means an acyl radical derived from anarylcarboxylic acid, “aryl” having the meaning given above. Examples ofsuch aroyl radicals include substituted and unsubstituted benzoyl ornapthoyl such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The terms “heterocyclo,” alone or in combination, means a saturated orpartially unsaturated monocyclic, bicyclic or tricyclic heterocycleradical containing at least one nitrogen, oxygen or sulfur atom ringmember and having preferably 3 to 8 ring members in each ring, morepreferably 3 to 7 ring members in each ring and most preferably 5 to 6ring members in each ring. “Heterocyclo” is intended to includesulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, andcarbocyclic fused and benzo fused ring systems. Such heterocycloradicals may be optionally substituted on one or more carbon atoms byhalogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, heteroaryl,heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino,alkylsulfonylamino and the like, and/or on a secondary nitrogen atom(i.e., —NH—) by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl,heteroaralkyl, phenyl or phenylalkyl and/or on a tertiary nitrogen atom(i.e., ═N—) by oxido. “Heterocycloalkyl” means an alkyl radical asdefined above in which at least one hydrogen atom is replaced by aheterocyclo radical as defined above, such as pyrrolidinylmethyl,tetrahydrothienylmethyl, pyridylmethyl and the like. The term“heteroaryl”, alone or in combination, means an aromatic heterocycloradical as defined above, which is optionally substituted as definedabove with respect to the definitions of aryl and heterocyclo. Examplesof such heterocyclo and heteroaryl groups are pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g.,imidazol 4-yl, 1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl,pyridyl, (e.g. 2-(1-piperidinyl)pyridyl and 2-4-benzylpiperazin-1-yl-1-pyridinyl, etc.), pyrazinyl, pyrimidinyl, furyl,tetrahydrofuryl, thienyl, tetrahydrothienyl and its sulfoxide andsulfone derivatives, triazolyl, oxazolyl, thiazolyl, indolyl (e.g.2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g. 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl. (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-,4- or 5-benzimidazolyl,methylenedioxyphen-4-yl, methylenedioxyphen-5-yl, ethylenedioxyphenyl,benzothiazolyl, benzopyranyl, benzofuryl, 2,3-dihydrobenzofuryl,benzoxazolyl, thiophenyl and the like. The term“cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the meaning given above. The term“aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoylwherein aryl and alkanoyl have the meaning given above. The term“heterocycloalkoxycarbonyl” means an acyl group derived fromheterocycloalkyl-O—COOH wherein heterocycloalkyl is as defined above.The term “heterocycloalkanoyl” is an acyl radical derived from aheterocycloalkylcarboxylic acid wherein heterocyclo has the meaninggiven above. The term “heterocyclo alkoxycarbonyl” means an acyl radicalderived from a heterocycloalkyl-O—COOH wherein heterocyclo has themeaning given above. The term “heteroaryloxycarbonyl” means an acylradical derived from a carboxylic acid represented by heteroaryl-O—COOHwherein heteroaryl has the meaning given above. The term “aminocarbonyl”alone or in combination, means an amino-substituted carbonyl (carbamoyl)group wherein the amino group can be a primary, secondary or tertiaryamino group containing substituents selected from alkyl, and, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkylcarboxylic acid wherein the amino group can be a primary, secondaryor tertiary amino group containing substituents selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. Theterm “halogen” means fluorine, chlorine, bromine or iodine. The term“haloalkyl” means an alkyl radical having the meaning as defined abovewherein one or more hydrogens are replaced with a halogen. Examples ofsuch haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl andthe like. The term “leaving group” (L or W) generally refers to groupsreadily displaceable by a nucleophile, such as an amine, a thiol or analcohol nucleophile. Such leaving groups are well known in the art.Examples of such leaving groups include, but are not limited to,N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R). However, such procedures are generally applicableto those compounds of opposite configuration, e.g., where thestereochemistry about the hydroxyl group is (S). In addition, thecompounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedures asschematically shown in Schemes I and II.

An N-protected chloroketone derivative of an amino acid having theformula:

wherein P represents an amino protecting group, and R² is as definedabove, is reduced to the corresponding alcohol utilizing an appropriatereducing agent. Suitable amino protecting groups are well known in theart and include carbobenzoxy, t-butoxycarbonyl, and the like. Apreferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is reacted, preferably at room temperature, with a suitablebase in a suitable solvent system to produce an N-protected aminoepoxide of the formula:

wherein P and R² are as defined above. Suitable solvent systems forpreparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared, such as inco-owned and co-pending PCT Patent Application Serial No. PCT/US93/04804(WO 93/23388) and PCT/US94/12201, and US Patent Application Ser. No.08/376,340, each of which is incorporated herein by reference in theirentirety) disclose methods of preparing chiral epoxide, chiralcyanohydrin, chiral amine and other chiral intermediates useful in thepreparation of retroviral protease inhibitors, starting with a DL-, D-or L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected amino acid ester.For the purposes of illustration, a protected L-amino acid with thefollowing formula will be used to prepare the inhibitors of thisinvention:

wherein P³ represents carboxyl-protecting group, e.g., methyl, ethyl,benzyl, tertiary-butyl, 4-methoxyphenylmethyl and the like; R² is asdefined above; and P¹ and P² independently are selected from amineprotecting groups, including but not limited to, aralkyl, substitutedaralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl,substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl.Examples of aralkyl include, but are not limited to benzyl,ortho-methylbenzyl, trityl and benzhydryl, which can be optionallysubstituted with halogen, alkyl of C₁-C₈, alkoxy, hydroxy, nitro,alkylene, amino, alkylamino, acylamino and acyl, or their salts, such asphosphonium and ammonium salts. Examples of aryl groups include phenyl,naphthalenyl, indanyl, anthracenyl, durenyl, 9-(9-phenylfluorenyl) andphenanthrenyl, cycloalkenylalkyl or substituted cycloalkylenylalkylradicals containing cycloalkyls of C₆-C₁₀. Suitable acyl groups includecarbobenzoxy, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substitutedbenzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyland the like. Preferably P¹ and P² are independently selected fromaralkyl and substituted aralkyl. More preferably, each of P¹ and P² isbenzyl.

Additionally, the P¹ and/or P² protecting groups can form a heterocyclicring with the nitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, e.g., nitrophthalimidyl.The term silyl refers to a silicon atom optionally substituted by one ormore alkyl, aryl and aralkyl groups.

Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. Preferred reducing agents includelithium aluminium hydride, lithium borohydride, sodium borohydride,borane, lithium tri-ter-butoxyaluminum hydride, borane/THF complex. Mostpreferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H)in toluene. The resulting alcohol is then converted, for example, by wayof a Swern oxidation, to the corresponding aldehyde of the formula:

wherein P¹, P² and R² are as defined above. Thus, a dichloromethanesolution of the alcohol is added to a cooled (−75 to −68° C.) solutionof oxalyl chloride in dichloromethane and DMSO in dichloromethane andstirred for 35 minutes.

Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO or tetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutyl chloroformate and DMSO. The oxidation conditions reportedby Reetz et al [Angew Chem., 99, p. 1186, (1987)], Angew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at −78° C.

The preferred oxidation method described in this invention is sulfurtrioxide pyridine complex, triethylamine and DMSO at room temperature.This system provides excellent yields of the desired chiral protectedamino aldehyde usable without the need for purification i.e., the needto purify kilograms of intermediates by chromatography is eliminated andlarge scale operations are made less hazardous. Reaction at roomtemperature also eliminated the need for the use of low temperaturereactor which makes the process more suitable for commercial production.

The reaction may be carried out under an inert atmosphere such asnitrogen or argon, or normal or dry air, under atmospheric pressure orin a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either P¹ orP²=H] or N,N-disubstituted aldehyde.

In addition, hydride reduction of an amide or ester derivative of thecorresponding benzyl (or other suitable protecting group) nitrogenprotected phenylalanine, substituted phenylalanine or cycloalkyl analogof phenylalanine derivative can be carried out to provide the aldehydes.Hydride transfer is an additional method of aldehyde synthesis underconditions where aldehyde condensations are avoided, cf, OppenauerOxidation.

The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about −20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

Alternatively, an acid chloride derivative of a protected phenylalanineor phenylalanine derivative as disclosed above can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction).

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. A D-amino acid can be utilized in place ofthe L-amino acid in order to prepare compounds having an (S)stereochemistry at the carbon bonded to R².

The addition of chloromethylithium or bromomethylithium to a chiralamino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about −80° C. to 0° C. but preferablybetween about −80° C. to −20° C. The most preferred reactiontemperatures are between −40° C. to −15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

Alternative methods of conversion to the epoxides of this inventioninclude substitution of other charged methylenation precurser speciesfollowed by their treatment with base to form the analogous anion.Examples of these species include trimethylsulfoxonium tosylate ortriflate, tetramethylammonium halide, methyldiphenylsulfoxonium halidewherein halide is chloride, bromide or iodide.

The conversion of the aldehydes of this invention into their epoxidederivative can also be carried out in multiple steps. For example, theaddition of the anion of thioanisole prepared from, for example, a butylor aryl lithium reagent, to the protected aminoaldehyde, oxidation ofthe resulting protected aminosulfide alcohol with well known oxidizingagents such as hydrogen peroxide, tert-butyl hypochlorite, bleach orsodium periodate to give a sulfoxide. Alkylation of the sulfoxide with,for example, methyl iodide or bromide, methyl tosylate, methyl mesylate,methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride orthe like, in the presence of an organic or inorganic base Alternatively,the protected aminosulfide alcohol can be alkylated with, for example,the alkylating agents above, to provide a sulfonium salts that aresubsequently converted into the subject epoxides with tert-amine ormineral bases.

The desired epoxides formed, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare retroviralprotease inhibitors. The foregoing process is applicable to mixtures ofoptical isomers as well as resolved compounds. If a particular opticalisomer is desired, it can be selected by the choice of startingmaterial, e.g., L-phenylalanine, D-phenylalanine, L-phenylalaninol,D-phenylalaninol, D-hexahydrophenylalaninol and the like, or resolutioncan occur at intermediate or final steps. Chiral auxiliaries such as oneor two equivilants of camphor sulfonic acid, citric acid, camphoricacid, 2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of the formulaR³NH₂, wherein R³ is hydrogen or is as defined above. The reaction canbe conducted over a wide range of temperatures, e.g., from about 10° C.to about 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. The resulting product is a3-(N-protected amino)-3-(R²)-1-(NHR³)-propan-2-ol derivative(hereinafter referred to as an amino alcohol) can be represented by theformulas:

wherein P, P¹, P², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith the sulfonyl chloride R⁴SO₂Cl, the sulfonyl bromide R⁴SO₂Br or thecorresponding sulfonyl anhydride, preferably in the presence of an acidscavenger. Suitable solvents in which the reaction can be conductedinclude methylene chloride, tetrahydrofuran and the like. Suitable acidscavengers include triethylamine, pyridine and the like. The resultingsulfonamide derivative can be represented, depending on the epoxideutilized by the formulas

wherein P, P¹, P², R², R³ and R⁴ are as defined above. Theseintermediates are useful for preparing inhibitor compounds of thepresent invention.

The sulfonyl halides of the formula R⁴SO₂X can be prepared by thereaction of a suitable aryl, heteroaryl and benzo fused heterocycloGrignard or lithium reagents with sulfuryl chloride, or sulfur dioxidefollowed by oxidation with a halogen, preferably chlorine. Aryl,heteroaryl and benzo fused heterocyclo Grignard or lithium reagents canbe prepared from their corresponding halide (such as chloro or bromo)compounds which are commercially available or readily prepared fromcommercially available starting materials using known methods in theart. Also, thiols may be oxidized to sulfonyl chlorides using chlorinein the presence of water under carefully controlled conditions.Additionally, sulfonic acids, such as arylsulfonic acids, may beconverted to sulfonyl halides using reagents such as PCl₅, SOCl₂,ClC(O)C(O)Cl and the like, and also to anhydrides using suitabledehydrating reagents. The sulfonic acids may in turn be prepared usingprocedures well known in the art. Some sulfonic acids are commerciallyavailable. In place of the sulfonyl halides, sulfinyl halides (R⁴SOX) orsulfenyl halides (R⁴SX) can be utilized to prepare compounds wherein the—SO₂— moiety is replaced by an —SO— or —S— moiety, respectively.Arylsulfonic acids, benzo fused heterocyclo sulfonic acids or heteroarylsulfonic acids can be prepared by sulfonation of the aromatic ring bywell known methods in the art, such as by reaction with sulfuric acid,SO₃, SO₃ complexes, such as DMF(SO₃), pyridine(SO₃),N,N-dimethylacetamide(SO₃), and the like. Preferably, arylsulfonylhalides are prepared from aromatic compounds by reaction with DMF(SO₃)and SOCl₂ or ClC(O)C(O)Cl. The reactions may be performed stepwise or ina single pot.

Arylsulfonic acids, benzo fused heterocyclo sulfonic acids, heteroarylsulfonic acids, arylmercaptans, benzo fused heterocyclo mercaptans,heteroarylmercaptans, arylhalides, benzo fused heterocyclo halides,heteroarylhalides, and the like are commercially available or can bereadily prepared from starting materials commercially available usingstandard methods well known in the art. For example, a number ofsulfonic acids (R⁴SO₃H) represented by the formulas

wherein A, B, Z, R⁶, R⁷ and R⁹ are as defined above, have been preparedfrom 1,2-benzenedithiol, 2-mercaptanphenol, 1,2-benzenediol,2-aminobenzothiazole, benzothiazole, 2-aminobenzimidazole,benzimidazole, and the like, which are commercially available, byCarter, U.S. Pat. No. 4,595,407; Ehrenfreund et al., U.S. Pat. No.4,634,465; Yoder et al., J. Heterocycl. Chem. 4:166-167 (1967); Cole etal., Aust. J. Chem. 33:675-680 (1980); Cabiddu et al., Synthesis 797-798(1976); Ncube et al., Tet. Letters 2345-2348 (1978); Ncube et al., Tet.Letters 255-256 (1977); Ansink & Cerfontain, Rec. Trav. Chim. Pays-Bas108:395-403 (1989); and Kajihara & Tsuchiya, EP 638564 A1, each of whichare incorporated herein by reference in their entirety. For example,1,2-benzenedithiol, 2-mercaptanphenol or 1,2-benzenediol can be reactedwith R⁶R⁷C(L′)₂, where L′ is as defined below, preferably, Br or I, inthe presence of a base, such as hydroxide, or R⁶R⁷C═O in the presence ofacid, such as toluenesulfonic acid, or P₂O₅, to prepare the substitutedbenzo fused heterocycle of formula

which can then be sulfonylated to the sulfonic acid above. For example,CF₂Br₂ or CD₂Br₂ can be reacted with 1,2-benzenedithiol,2-mercaptanphenol or 1,2-benzenediol in the presence of base to producethe compounds

respectively, wherein A and B are O or S and D is a deuterium atom.Also, when A and/or B represent S, the sulfur can be oxidized using themethods described below to the sulfone or sulfoxide derivatives.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.

Following neutralization of the salt, the amine is then coupled to theDL-, D-, or L-amino acid corresponding to the formula PNHCH(R¹)COOH,wherein P and R¹ are as defined above, followed by deprotection of theamine as described above, and coupling to

wherein R¹⁰ and R¹¹ are as defined above, W is a leaving group, such asmesylate, bromo or chloro, and L is leaving group such as halide,anhydride, active ester, and the like. For example when R¹⁰ and R¹¹ areboth hydrogen radical, bromoacetyl halide, chloroacetyl halide or thecorresponding anhydride can be used. Finally, reacting the aboveintermediate with the amine R¹²R¹³NH can produce the antiviral compoundsof the present invention having the formula

wherein R¹, R², R³, R⁴, R¹⁰, R¹¹, R¹² and R¹³ are as defined above.Amines of the formula R¹²R¹³NH are commercially available, such asdimethylamine, isobutylamine, isopropylamine, benzylamine, and the like;or can readily be prepared from commercially available startingmaterials using standard methods well known in the art.

Alternatively, following neutralization of the salt, the amine offormula

is then coupled to the DL-, D-, or L-amino acid corresponding to theformula PNHCH(R¹)COOH, wherein P and R¹ are as defined above, followedby deprotection of the amine as described above and then coupling thedeprotected amine to the amino acid of formula

or specific stereoisomer thereof, wherein R¹⁰, R¹¹, R¹², and R¹³ are asdefined above, such as N-methylalanine, N,N-dimethylalanine,N,N,2,2-tetramethylglycine, N-benzylserine and the like, to produce theantiviral compounds of the present invention. The amino acids arecommercially available or are readily prepared from a protectedcarboxylic acid with a leaving group W (defined above),W—(R¹⁰)(R¹¹)C—CO₂P³, by reaction with the amine R¹²R¹³NH as shown inScheme III, wherein P³, R¹⁰, R¹¹, R¹², and R¹³ are as defined above.

Alternatively, following neutralization of the salt, the amine offormula

is then coupled to the DL-, D-, or L-amino acid corresponding to theformula

wherein R¹, R¹⁰, R¹¹, R¹², and R¹³ are as defined above, which can beprepared in a similar fashion to the coupling methods described abovefrom DL-, D-, or L-amino acid corresponding to the formulaNH₂CH(R¹)COOP³, wherein P³ and R¹ are as defined above.

The DL-, D-, or L-amino acid corresponding to the formula PNHCH(R¹)COOHor NH₂CH(R)COOP³, wherein P, P³ and R¹ are as defined above, arecommercially available (Sigma Chemical Co.), or readily prepared usingstandard methods well known in the art from readily available startingmaterials. Preferably, P is a benzyloxycarbonyl or t-butoxycarbonylradical and P³ is benzyl or tert-butyl radicals. Standard couplingprocedures can be used to couple the amino acids and amines. Thecarboxylic acid group is reacted to form an anhydride, mixed anhydride,acid halide, such as chloride or bromide, or active ester, such asesters of N-hydroxysuccinimide, HOBT and the like, using well knownprocedures and conditions. Appropriate solvent systems includetetrahydrofuran, ethylether, methyl-tert-butylether, methylene chloride,N,N-dimethylformamide and the like, including mixtures thereof.

Alternatively, the protected amino alcohol from the epoxide opening canbe further protected at the newly introduced amino group with aprotecting group P′ which is not removed with the removal of the aminoprotecting groups P or P¹ and P². One skilled in the art can chooseappropriate combinations of P′, P, P¹ and P². For example, suitablecombinations are P=Cbz and P′=Boc; P′=Cbz and P=Boc; P¹=Cbz, P²=benzyland P′=Boc; and P¹=P²=benzyl and P′=Boc. The resulting compoundrepresented by the formula

can be carried through the remainder of the synthesis to provide acompound of the formula

wherein P′, R¹, R², R³, R¹⁰, R¹¹, R¹², and R¹³ are as defined above. Theprotecting group P′ is then selectively removed and the resulting amineis reacted with the sulfonyl chloride R⁴SO₂Cl, the sulfonyl bromideR⁴SO₂Br or the corresponding sulfonyl anhydride, preferably in thepresence of an acid scavenger, to form the compounds of the presentinvention. This selective deprotection and conversion to the sulfonamidecan be accomplished at either the end of the synthesis or at anyappropriate intermediate step if desired.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art. e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples illustrate the preparation of inhibitor compoundsof the present invention and intermediates useful in preparing theinhibitor compounds of the present invention.

EXAMPLE 1

Preparation of 2S-[Bis(phenylmethyl)amino]benzenepropanolMethod 1: 2S-[Bis(phenylmethyl)amino]benzenepropanol from the DIBALReduction of N,N-bis(phenylmethyl)-L-Phenylalanine phenylmethyl esterStep 1:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 mL) was heated to 97° C. Benzyl bromide (108.5 mL, 0.605 mol) wasthen slowly added (addition time—25 min). The mixture was stirred at 97°C. for 30 minutes under a nitrogen atmosphere. The solution was cooledto room temperature and extracted with toluene (2×250 mL). The combinedorganic layers were washed with water and brine, dried over magnesiumsulfate, filtered and concentrated to an oil. The identity of theproduct was confirmed as follows. Analytical TLC (10% ethylacetate/hexane, silica gel) showed major component at Rf value=0.32 tobe the desired tribenzylated compound,N,N-bis(phenylmethyl)-L-phenylalanine phenylmethyl ester. This compoundcan be purified by column chromatography (silica gel, 15% ethylacetate/hexane). Usually the product is pure enough to be used directlyin the next step without further purification. ¹H NMR spectrum was inagreement with published literature. ¹H NMR (CDCL₃) ∂, 3.00 and 3.14(ABX-system, 2H, J_(AB)=14.1 Hz, J_(AX)=7.3 Hz and J_(BX)=5.9 Hz), 3.54and 3.92 (AB-System, 4H, J_(AB)=13.9 Hz), 3.71 (t, 1H, J=7.6 Hz), 5.11and 5.23 (AB-System, 2H, J_(AB)=12.3 Hz), and 7.18 (m, 20H). EIMS: m/z434 (M−1).

Step 2:

The benzylated phenylalanine phenylmethyl ester (0.302 mol) from theprevious reaction was dissolved in toluene (750 mL) and cooled to −55°C. A 1.5 M solution of DIBAL in toluene (443.9 mL, 0.666 mol) was addedat a rate to maintain the temperature between −55 to −50° C. (additiontime—1 hr). The mixture was stirred for 20 minutes under a nitrogenatmosphere and then quenched at −55° C. by the slow addition of methanol(37 ml). The cold solution was then poured into cold (5° C.) 1.5 N HClsolution (1.8 L). The precipitated solid (approx. 138 g) was filteredoff and washed with toluene. The solid material was suspended in amixture of toluene (400 mL) and water (100 ml). The mixture was cooledto 5° C. and treated with 2.5 N NaOH (186 mL) and then stirred at roomtemperature until solid dissolved. The toluene layer was separated fromthe aqueous phase and washed with water and brine, dried over magnesiumsulfate, filtered and concentrated to a volume of 75 mL (89 g). Ethylacetate (25 mL) and hexane (25 mL) were added to the residue upon whichthe desired alcohol product began to crystallize. After 30 min, anadditional 50 mL hexane were added to promote further crystallization.The solid was filtered off and washed with 50 mL hexane to give 34.9 gof first crop product. A second crop of product (5.6 g) was isolated byrefiltering the mother liquor. The two crops were combined andrecrystallized from ethyl acetate (20 mL) and hexane (30 mL) to give 40g of βS-2-[Bis(phenyl-methyl)amino]benzenepropanol, 40% yield fromL-phenylalanine. An additional 7 g (7%) of product can be obtained fromrecrystallization of the concentrated mother liquor. TLC of productRf=0.23 (10% ethyl acetate/hexane, silica gel); ¹H NMR (CDCl₃) ∂ 2.44(m, 1H), 3.09 (m, 2H), 3.33 (m, 1H), 3.48 and 3.92 (AB-System, 4H,J_(AB)=13.3 Hz), 3.52 (m, 1H) and 7.23 (m, 15H); [α]D²⁵ +42.4 (c 1.45,CH₂Cl₂); DSC 77.67° C.; Anal. Calcd. for C₂₃H₂₅ON: C, 83.34; H, 7.60; N,4.23. Found: C, 83.43; H, 7.59; N, 4.22. HPLC on chiral stationaryphase: Cyclobond I SP column (250×4.6 mm I.D.), mobile phase:methanol/triethyl ammonium acetate buffer pH 4.2 (58:42, v/v), flow-rateof 0.5 ml/min, detection with detector at 230 nm and a temperature of 0°C. Retention time: 11.25 min., retention time of the desired productenantiomer: 12.5 min.

Method 2: Preparation of βS-2-[Bis(phenylmethyl)amino]benzene-propanolfrom the N,N-Dibenzylation of L-Phenylalaninol

L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnight to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at −8° C.), washed with 1.6 L of cold (−10° C.) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) ofβS-2-[Bis(phenylmethyl)amino]benzene-propanol, Mp=71.5-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed in Method 1.

EXAMPLE 2

Preparation of 2S-[Bis(phenylmethyl)amino]benzenepropanaldehydeMethod 1:

2S-[Bis(phenylmethyl)amino]benzene-propanol (200 g, 0.604 mol) wasdissolved in triethylamine (300 mL, 2.15 mol). The mixture was cooled to12° C. and a solution of sulfur trioxide/pyridine complex (380 g, 2.39mol) in DMSO (1.6 L) was added at a rate to maintain the temperaturebetween 8-17° C. (addition time—1.0 h). The solution was stirred atambient temperature under a nitrogen atmosphere for 1.5 hour at whichtime the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenched with 1.6 L of cold water (10-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35-40°C. and then dried under vacuum to give 198.8 g of2S-[Bis-(phenylmethyl)amino]-benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. [α]D²⁵=−92.9° (c1.87, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15 (ABX-System, 2H,J_(AB)=13.9 Hz, J_(AX)=7.3 Hz and J_(BX)=6.2 Hz), 3.56 (t, 1H, 7.1 Hz),3.69 and 3.82 (AB-System, 4H, J_(AB)=13.7 Hz), 7.25 (m, 15H) and 9.72(s, 1H); HRMS Calcd for (M+1) C₂₃H₂₄NO 330.450, found: 330.1836. Anal.Calcd. for C₂₃H₂₃ON: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64; H,7.42; N, 4.19. HPLC on chiral stationary phase:(S,S) PirkleWhelk-O 1column (250×4.6 mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5,v/v), flow-rate: 1.5 ml/min, detection with UV detector at 210 nm.Retention time of the desired S-isomer: 8.75 min., retention time of theR-enantiomer 10.62 min.

Method 2:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at −74° C. (addition time ˜1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution ofβS-2-[bis(phenylmethyl)amino]benzene-propanol (0.074 mol) in 100 ml ofdichloromethane (addition time—20 min., temp. −75° C. to −68° C.). Thesolution was stirred at −78° C. for 35 minutes under a nitrogenatmosphere. Triethylamine (41.2 ml, 0.295 mol) was then added over 10min. (temp. −78° to −68° C.) upon which the ammonium salt precipitated.The cold mixture was stirred for 30 min. and then water (225 ml) wasadded. The dichloromethane layer was separated from the aqueous phaseand washed with water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give αS-[bis(phenylmethyl)amino]benzenepropanaldehyde.The aldehyde was carried on to the next step without purification.

Method 3:

To a mixture of 1.0 g (3.0 mmoles) ofβS-2-[bis(phenylmethyl)amino]benzenepropanol 0.531 g (4.53 mmoles) ofN-methyl morpholine, 2.27 g of molecular sieves (4A) and 9.1 mL ofacetonitrile was added 53 mg (0.15 mmoles) of tetrapropylammoniumperruthenate(TPAP). The mixture was stirred for 40 minutes at roomtemperature and concentrated under reduced pressure. The residue wassuspended in 15 mL of ethyl acetate, filtered through a pad of silicagel. The filtrate was concentrated under reduced pressure to give aproduct containing approximately 50% ofαS-2-[bis(phenylmethyl)amino]benzene propanaldehyde as a pale yellowoil.

Method 4:

To a solution of 1.0 g (3.02 mmoles) ofβS-2-[bis(phenylmethyl)amino]benzenepropanol in 9.0 mL of toluene wasadded 4.69 mg (0.03 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy,free radical (TEMPO), 0.32 g (3.11 mmoles) of sodium bromide, 9.0 mL ofethyl acetate and 1.5 mL of water. The mixture was cooled to 0° C. andan aqueous solution of 2.87 mL of 5% household bleach containing 0.735 g(8.75 mmoles) of sodium bicarbonate and 8.53 mL of water was addedslowly over 25 minutes. The mixture was stirred at 0° C. for 60 minutes.Two more additions (1.44 mL each) of bleach was added followed bystirring for 10 minutes. The two phase mixture was allowed to separate.The aqueous layer was extracted twice with 20 mL of ethyl acetate. Thecombined organic layer was washed with 4.0 mL of a solution containing25 mg of potassium iodide and water (4.0 mL), 20 mL of 10% aqueoussodium thiosulfate solution and then brine solution. The organicsolution was dried over magnesium sulfate, filtered and concentratedunder reduced pressure to give 1.34 g of crude oil containing a smallamount of the desired product aldehyde,αS-(bis(phenylmethyl)amino]benzenepropanaldehyde.

Method 5:

Following the same procedures as described in Method 1 of this Exampleexcept 3.0 equivalents of sulfur trioxide pyridine complex was used andαS-[bis(phenylmethyl)amino]benzenepropanaldehyde was isolated incomparable yields.

EXAMPLE 3

Preparation of N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutaneMethod 1:

A solution of αS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (191.7g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperaturesuch as −70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyl lithium in hexane(1.6 M, 365 mL, 0.58 mol) was then added at a rate that maintained thetemperature below −25° C. After addition the mixture was stirred at −30to −35° C. for 10 minutes. More additions of reagents were carried outin the following manner: (1) additional chloroiodomethane (17 mL) wasadded, followed by n-butyl lithium (110 mL) at <−25° C. After additionthe mixture was stirred at −30 to −35° C. for 10 minutes. This wasrepeated once (2) Additional chloroiodomethane (8.5 mL, 0.11 mol) wasadded, followed by n-butyl lithium (55 mL, 0.088 mol) at <−25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11mol) was added, followed by n-butyl lithium (37 mL, 0.059 mol) at <−25°C. After addition the mixture was stirred at −30 to −35° C. for 10minutes. This was repeated once. The external cooling was stopped andthe mixture warmed to ambient temp. over 4 to 16 hours when TLC (silicagel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR: (2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tic analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

N,N,αS-Tris(phenylmethyl)-29-oxiranemethanamine

¹H NMR (400 MHz, CDCl₃) ∂ 2.49 and 2.51 (AB-System, 1H, J_(AB)=2.82),2.76 and 2.77 (AB-System, 1H, J_(AB)=4.03), 2.83 (m, 2H), 2.99 & 3.03(AB-System, 1H, J_(AB)=10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84 (AB-System,4H, J_(AB)=14.00), 7.21 (m, 15H); ¹³C NMR (400 MHz, CDCl₃) ∂ 139.55,129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13,45.99, 33.76; HRMS Calcd for C₂₄H₂₆NO (M+1) 344.477, found 344.2003.

N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine

¹H NMR (300 MHz, CDCl₃) ∂ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97(m, 1H), 3.14 (m, 1H), 3.85 (AB-System, 4H), 7.25 (m, 15H), HPLC onchiral stationary phase: Pirkle-Whelk-O 1 column (250×4.6 mm I.D.),mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of (8): 9.38 min.,retention time of enantiomer of (4): 13.75 min.

Method 2:

A solution of the crude aldehyde 0.074 mmol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) was cooled to −78° C., undera nitrogen atmosphere. A 1.6 M solution of n-butyl lithium in hexane (25ml, 0.040 mol) was then added at a rate to maintain the temperature at−75° C. (addition time—15 min.). After the first addition, additionalchloroiodomethane (1.6 ml, 0.022 mol) was added again, followed byn-butyl lithium (23 ml, 0.037 mol), keeping the temperature at −75° C.The mixture was stirred for 15 min. Each of the reagents,chloroiodomethane (0.70 ml, 0.010 mol) and n-butyl lithium (5 ml, 0.008mol) were added 4 more times over 45 min at −75° C. The cooling bath wasthen removed and the solution warmed to 22° C. over 1.5 hr. The mixturewas poured into 300 ml of saturated aq ammonium chloride solution. Thetetrahydrofuran layer was separated. The aqueous phase was extractedwith ethyl acetate (1×300 ml) The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered and concentrated togive a brown oil (27.4 g). The product could be used in the next stepwithout purification. The desired diastereomer can be purified byrecrystallization at a subsequent step. The product could also bepurified by chromatography.

Method 3:

A solution of αS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (178.84g, 0.54 mol) and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran(1.8 L) was cooled to −30 to −35° C. (colder temperature such as −70° C.also worked well but warmer temperatures are more readily achieved inlarge scale operations) in a stainless steel reactor under a nitrogenatmosphere. A solution of n-butyl lithium in hexane (1.6 M, 340 mL, 0.54mol) was then added at a rate that maintained the temperature below −25°C. After addition the mixture was stirred at −30 to −35° C. for 10minutes. More additions of reagents were carried out in the followingmanner: (1) additional bromochloromethane (14 mL) was added, followed byn-butyl lithium (102 mL) at <−25° C. After addition the mixture wasstirred at −30 to −35° C. for 10 minutes. This was repeated once. (2)Additional bromochloromethane (7 mL, 0.11 mol) was added, followed byn-butyl lithium (51 mL, 0.082 mol) at <−25° C. After addition themixture was stirred at −30 to −35° C. for 10 minutes. This was repeated5 times. (3) Additional bromochloromethane (7 mL, 0.11 mol) was added,followed by n-butyl lithium (51 mL, 0.082 mol) at <−25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated once. The external cooling was stopped and the mixturewarmed to ambient temp. over 4 to 16 hours when TLC (silica gel, 20%ethyl acetate/hexane) indicated that the reaction was completed. Thereaction mixture was cooled to 10° C. and quenched with 1452 g of 16%ammonium chloride solution (prepared by dissolving 232 g of ammoniumchloride in 1220 mL of water), keeping the temperature below 23° C. Themixture was stirred for 10 minutes and the organic and aqueous layerswere separated. The aqueous phase was extracted with ethyl acetate(2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material.

Method 4:

Following the same procedures as described in Method 3 of this Exampleexcept the reaction temperatures were at −20° C. The resultingN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was a diastereomericmixture of lesser purity then that of Method 3.

Method 5:

Following the same procedures as described in Method 3 of this Exampleexcept the reaction temperatures were at −70-−78° C. The resultingN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was a diastereomericmixture, which was used directly in the subsequent steps withoutpurification.

Method 6:

Following the same procedures as described in Method 3 of this Exampleexcept a continuous addition of bromochloromethane and n-butyl lithiumwas used at −30 to −35° C. After the reaction and work up procedures asdescribed in Method 3 of this Example, the desiredN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was isolated incomparable yields and purities.

Method 7:

Following the same procedures as described in Method 2 of this Exampleexcept dibromomethane was used instead of chloroiodomethane. After thereaction and work up procedures as described in Method 2 of thisExample, the desired N,N,αS-tris(phenylmethyl)-2S-oxirane-methanaminewas isolated.

EXAMPLE 4

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine

To a solution of crudeN,N-dibenzyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane (388.5 g, 1.13 mol)in isopropanol (2.7 L) (or ethyl acetate) was added isobutylamine (1.7kgm, 23.1 mol) over 2 min. The temperature increased from 25° C. and to30° C. The solution was heated to 82° C. and stirred at this temperaturefor 1.5 hours. The warm solution was concentrated under reduced pressureat 65° C. The brown oil residue was transferred to a 3-L flask and driedin vacuo (0.8 mm Hg) for 16 h to give 450 g of3S-[N,N-bis(phenylmethyl)amino-4-phenylbutan-2R-ol as a crude oil.

An analytical sample of the desired major diastereomeric product wasobtained by purifying a small sample of crude product by silica gelchromatography (40% ethyl acetate/hexane). Tlc analysis: silica gel, 40%ethyl acetate/hexane; Rf=0.28; HPLC analysis: ultrasphere ODS column,25% triethylamino-/phosphate buffer pH 3-acetonitrile, flow rate 1mL/min, UV detector; retention time 7.49 min.; HRMS Calcd for C₂₈H₂₇N₂O(M+1) 417.616, found 417.2887. An analytical sample of the minordiastereomeric product,3S-[N,N-bis(phenylmethyl)amino]1-(2-methylpropyl)amino-4-phenylbutan-2S-olwas also obtained by purifying a small sample of crude product by silicagel chromatography (40% ethyl acetate/hexane).

EXAMPLE 5

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine-oxalicacid salt

To a solution of oxalic acid (8.08 g, 89.72 mmol) in methanol (76 mL)was added a solution of crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(39.68 g, which contains about 25.44 g (61.06 mmol) of 3(S),2(R) isomerand about 4.49 g (10.78 mmol) of 3(S),2(S) isomer) in ethyl acetate (90mL) over 15 minutes. The mixture was stirred at room temperature forabout 2 hours. Solid was isolated by filtration, washed with ethylacetate (2×20 mL) and dried in vacuo for about 1 hour to yield 21.86 g(70.7% isomer recovery) of 97% diastereomerically pure salt (based onHPLC peak areas). HPLC analysis: Vydec-peptide/protein C18 column, UVdetector 254 nm, flow rate 2 mL/min., gradient (A=0.05% trifluoroaceticacid in water, B=0.05% trifluoroacetic acid in acetonitrile, 0 min. 75%A/25% B, 30 min. 10% A/90% B, 35 min. 10% A/90% B, 37 min. 75% A/25% B);Retention time 10.68 min. (3(S),2(R) isomer) and 9.73 min. (3(S),2(S)isomer). Mp=174.99° C.; Microanalysis: Calc.: C, 71.05%; H, 7.50%; N,5.53%. Found: C, 71.71%; H, 7.75%; N, 5.39%.

Alternatively, oxalic acid dihydrate (119 g, 0.94 mole) was added to a5000 mL round bottom flask fitted with a mechanical stirrer and adropping funnel. Methanol (1000 ml) was added and the mixture stirreduntil dissolution was complete. A solution of crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol in ethyl acetate (1800 ml, 0.212 g aminoalcohol isomers/mL, 0.9160 moles) was added over a twenty minute period.The mixture was stirred for 18 hours and the solid product was isolatedby centrifugation in six portions at 400 G. Each portion was washed with125 mL of ethyl acetate. The salt was then collected and dried overnightat 1 torr to yield 336.3 g of product (71% based upon total aminoalcohol). HPLC/MS (electrospray) was consistent with the desired product(m/z 417 [M+H]⁺).

Alternatively, crude 3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol (5 g) was dissolvedin methyl-tert-butylether (MTBE) (10 mL) and oxalic acid (1 g) inmethanol (4 mL) was added. The mixture was stirred for about 2 hours.The resulting solid was filtered, washed with cold MTBE and dried toyield 2.1 g of white solid of about 98.9% diastereomerically pure (basedon HPLC peak areas).

EXAMPLE 6

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.aceticacid salt

To a solution of crude 3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol inmethyl-tert-butylether (MTBE) (45 mL, 1.1 g amino alcohol isomers/mL)was added acetic acid (6.9 mL) dropwise. The mixture was stirred forabout 1 hour at room temperature. The solvent was removed in vacuo toyield a brown oil about 85% diastereomerically pure product (based onHPLC peak areas). The brown oil was crystallized as follows: 0.2 g ofthe oil was dissolved in the first solvent with heat to obtain a clearsolution, the second solvent was added until the solution became cloudy,the mixture was heated again to clarity, seeded with about 99%diastereomerically pure product, cooled to room temperature and thenstored in a refrigerator overnight. The crystals were filtered, washedwith the second solvent and dried. The diastereomeric purity of thecrystals was calculated from the HPLC peak areas. The results are shownin Table 1.

TABLE 1 Diastereo- First Second Solvent Recovery meric Solvent SolventRatio Weight (g) Purity (%) MTBE Heptane 1:10 0.13 98.3 MTBE Hexane 1:100.03 99.6 Methanol Water 1:1.5 0.05 99.5 Toluene Heptane 1:10 0.14 98.7Toluene Hexane 1:10 0.10 99.7

Alternatively, crude 3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2 (R)-ol (50.0 g, whichcontains about 30.06 g (76.95 mmol) of 3(S),2(R) isomer and about 5.66 g(13.58 mmol) of 3(S),2(S) isomer) was dissolved inmethyl-tert-butylether (45.0 mL). To this solution was added acetic acid(6.90 mL, 120.6 mmol) over a period of about 10 min. The mixture wasstirred at room temperature for about 1 hour and concentrated underreduced pressure. The oily residue was purified by recrystallizationfrom methyl-tert-butylether (32 mL) and heptane (320 mL). Solid wasisolated by filtration, washed with cold heptane and dried in vacuo forabout 1 hour to afford 21.34 g (58.2% isomer recovery) of 96%diastereomerically pure monoacetic acid salt (based on HPLC peak areas).Mp=105-106° C.; Microanalysis: Calc.: C, 75.53%; H, 8.39%; N, 5.87%.Found: C, 75.05%; H, 8.75%; N, 5.71%.

EXAMPLE 7

Preparation of N-[3 (S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.L-tartaric acid salt

Crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(10.48 g, which contains about 6.72 g (16.13 mmol) of 3(S),2(R) isomerand about 1.19 g (2.85 mmol) of 3(S),2(S) isomer) was dissolved intetrahydrofuran (10.0 mL). To this solution was added a solution ofL-tartaric acid (2.85 g, 19 mmol) in methanol (5.0 mL) over a period ofabout 5 min. The mixture was stirred at room temperature for about 10min. and concentrated under reduced pressure. Methyl-tert-butylether(20.0 mL) was added to the oily residue and the mixture was stirred atroom temperature for about 1 hour. Solid was isolated by filtration toafford 7.50 g of crude salt. The crude salt was purified byrecrystallization from ethyl acetate and heptane at room temperature toyield 4.13 g (45.2% isomer recovery) of 95% diastereomerically pureL-tartaric acid salt (based on HPLC peak areas). Microanalysis: Calc.:C, 67.76%; H, 7.41%; N, 4.94%. Found: C, 70.06%; H, 7.47%; N, 5.07%.

EXAMPLE 8

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.dihydrochloricacid salt

Crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(10.0 g, which contains about 6.41 g (15.39 mmol) of 3(S),2(R) isomerand about 1.13 g (2.72 mmol) of 3(S),2(S) isomer) was dissolved intetrahydrofuran (20.0 mL). To this solution was added hydrochloric acid(20 mL, 6.0 N) over a period of about 5 min. The mixture was stirred atroom temperature for about 1 hour and concentrated under reducedpressure. The residue was recrystallized from ethanol at 0° C. to yield3.20 g (42.7% isomer recovery) of 98% diastereomerically puredihydrochloric acid salt (based on HPLC peak areas). Microanalysis:Calc.: C, 68.64%; H, 7.76%; N, 5.72%. Found: C, 68.79%; H, 8.07%; N,5.55%.

EXAMPLE 9

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.toluenesulfonicacid salt

Crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(5.0 g, which contains about 3.18 g (7.63 mmol) of 3(S),2(R) isomer andabout 0.56 g (1.35 mmol) of 3(S),2(S) isomer) was dissolved inmethyl-tert-butylether (10.0 mL). To this solution was added a solutionof toluenesulfonic acid (2.28 g, 12 mmol) in methyl-tert-butylether (2.0mL) and methanol (2.0 mL) over a period of about 5 min. The mixture wasstirred at room temperature for about 2 hours and concentrated underreduced pressure. The residue was recrystallized frommethyl-tert-butylether and heptane at 0° C., filtered, washed with coldheptane and dried in vacuo to yield 1.85 g (40.0% isomer recovery) of97% diastereomerically pure monotoluenesulfonic acid salt (based on HPLCpeak areas).

EXAMPLE 10

Preparation ofN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine-methanesulfonicacid salt

Crude3(S)-[N,N-bis(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(10.68 g, which contains about 6.85 g (16.44 mmol) of 3(S),2(R) isomerand about 1.21 g (2.90 mmol) of 3(S),2(S) isomer) was dissolved intetrahydrofuran (10.0 mL). To this solution was added methanesulfonicacid (1.25 mL, 19.2° mmol). The mixture was stirred at room temperaturefor about 2 hours and concentrated under reduced pressure. The oilyresidue was recrystallized from methanol and water at 0° C., filtered,washed with cold methanol/water (1:4) and dried in vacuo to yield 2.40 g(28.5% isomer recovery) of 98% diastereomerically puremonomethanesulfonic acid salt (based on HPLC peak areas).

EXAMPLE 11

Preparation of N-benzyl-L-phenylalaninol

Method 1:

L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL ofmethanol under inert atmosphere, 35.52 g (0.592 moles) of glacial aceticacid and 50 mL of methanol was added followed by a solution of 62.83 g(0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture wascooled to approximately 15° C. and a solution of 134.6 g (2.14 moles) ofsodium cyanoborohydride in 700 mL of methanol was added in approximately40 minutes, keeping the temperature between 15° C. and 25° C. Themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated under reduced pressure and partitioned between 1 L of 2Mammonium hydroxide solution and 2 L of ether. The ether layer was washedwith 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500mL of brine and dried over magnesium sulfate for 1 hour. The ether layerwas filtered, concentrated under reduced pressure and the crude solidproduct was recrystallized from 110 mL of ethyl acetate and 1.3 L ofhexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a whitesolid.

Method 2:

L-Phenylalaninol (5 g, 33 mmoles) and 3.59 g (33.83 ales) ofbenzaldehyde were dissolved in 55 mL of 3A ethanol under inertatmosphere in a Parr shaker and the mixture was warmed to 60° C. for 2.7hours. The mixture was cooled to approximately 25° C. and 0.99 g of 5%platinum on carbon was added and the mixture was hydrogenated at 60 psiof hydrogen and 40° C. for 10 hours. The catalyst was filtered off, theproduct was concentrated under reduced pressure and the crude solidproduct was recrystallized from 150 mL of heptane to give 3.83 g (48%yield) of N-benzyl-L-phenylalaninol as a white solid.

EXAMPLE 12

Preparation of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninol

N-benzyl-L-phenylalaninol (2.9 g, 12 mmoles) was dissolved in 3 mL oftriethylamine and 27 mL of methanol and 5.25 g (24.1 mmoles) ofdi-tert-butyl dicarbonate was added. The mixture was warmed to 60° C.for 35 minutes and concentrated under reduced pressure. The residue wasdissolved in 150 mL of ethyl acetate and washed twice with 10 mL of cold(0-5° C.), dilute hydrochloric acid (pH 2.5 to 3), 15 mL of water, 10 mLof brine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product oil was purified by silica gelchromatography (ethyl acetate:hexane, 12:3 as eluting solvent) to give3.98 g (97% yield) of colorless oil.

EXAMPLE 13

Preparation of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal

Method 1:

To a solution of 0.32 g (0.94 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 2.8 mL of toluene wasadded 2.4 mg (0.015 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy,free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 mL ofethyl acetate and 0.34 mL of water. The mixture was cooled to 0° C. andan aqueous solution of 4.2 mL of 5% household bleach containing 0.23 g(3.0 mL, 2.738 mmoles) of sodium bicarbonate was added slowly over 30minutes. The mixture was stirred at 0° C. for 10 minutes. Three moreadditions (0.4 mL each) of bleach was added followed by stirring for 10minutes after each addition to consume all the stating material. The twophase mixture was allowed to separate. The aqueous layer was extractedtwice with 8 mL of toluene. The combined organic layer was washed with1.25 mL of a solution containing 0.075 g of potassium iodide, sodiumbisulfate (0.125 g) and water (1.1 mL), 1.25 mL of 10% aqueous sodiumthiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL ofbrine solution. The organic solution was dried over magnesium sulfate,filtered and concentrated under reduced pressure to give 0.32 g (100%yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.

Method 2:

To a solution of 2.38 g (6.98 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 3.8 mL (27.2 mmoles)of triethylamine at 10° C. was added a solution of 4.33 g (27.2 mmoles)of sulfur trioxide pyridine complex in 17 mL of dimethyl sulfoxide. Themixture was warmed to room temperature and stirred for one hour. Water(16 mL) was added and the mixture was extracted with 20 mL of ethylacetate. The organic layer was washed with 20 mL of 5% citric acid, 20mL of water, 20 mL of brine, dried over magnesium sulfate and filtered.The filtrate was concentrated under reduced pressure to give 2.37 g(100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.

EXAMPLE 14

Preparation of3(S)-[N-(t-butoxycarbonyl)-N-benzylamino]-1,2-(S)-epoxy-4-phenylbutaneMethod 1:

A solution of 2.5 g (7.37 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal and 0.72 mL ofchloroiodomethane in 35 mL of THF was cooled to −78° C. A 4.64 mL of asolution of n-butyllithium (1.6 M in hexane, 7.42 mmoles) was addedslowly, keeping the temperature below −70° C. The mixture was stirredfor 10 minutes between −70 to −75° C. Two additional portions of 0.22 mLof chloroiodomethane and 1.4 mL of n-butyllithium was added sequentiallyand the mixture was stirred for 10 minutes between −70 to −75° C. aftereach addition. Four additional portions of 0.11 mL of chloroiodomethaneand 0.7 mL of n-butyllithium was added sequentially and the mixture wasstirred for 10 minutes between −70 to −75° C. after each addition. Themixture was warmed to room temperature for 3.5 hours. The product wasquenched at below 5° C. with 24 mL of ice-cold water. The biphasiclayers were separated and the aqueous layer was extracted twice with 30mL of ethyl acetate. The combined organic layers was washed three timeswith 10 mL water, then with 10 mL brine, dried over sodium sulfate,filtered and concentrated under reduced pressure to give 2.8 g of ayellow crude oil. This crude oil (>100% yield) is a mixture of thediastereomeric epoxidesN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine. Thecrude mixture is used directly in the next step without purification.

Method 2:

To a suspension of 2.92 g (13.28 mmoles) of trimethylsulfoxonium iodidein 45 mL of acetonitrile was added 1.49 g (13.28 mmoles) of potassiumt-butoxide. A solution of 3.0 g (8.85 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 18 mL of acetonitrilewas added and the mixture was stirred at room temperature for one hour.The mixture was diluted with 150 mL of water and extracted twice with200 mL of ethyl acetate. The organic layers were combined and washedwith 100 mL water, 50 mL brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give 3.0 g of a yellow crude oil.The crude product was purified by silica gel chromatography (ethylacetate/hexane: 1:8 as eluting solvent) to give 1.02 g (32.7% yield) ofa mixture of the two diastereomersN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.

Method 3:

To a suspension of 0.90 g (4.42 mmoles) of trimethylsulfonium iodide in18 mL of acetonitrile was added 0.495 g (4.42 mmoles) of potassiumt-butoxide. A solution of 1.0 g (2.95 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 7 mL of acetonitrilewas added and the mixture was stirred at room temperature for one hour.The mixture was diluted with 80 mL of water and extracted twice with 80mL of ethyl acetate. The organic layers were combined and washed with100 mL water, 30 mL brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give 1.04 g of a yellow crudeoil. The crude product was a mixture of the two diastereomersN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine,

EXAMPLE 15

Preparation of 3S-[N-(t-Butoxycarbonyl)-N-(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol

To a solution of 500 mg (1.42 mmoles) of the crude epoxide (a mixture ofthe two diastereomersN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine) in0.98 mL of isopropanol was added 0.71 mL (7.14 mmoles) of isobutylamine.The mixture was warmed to reflux at 85° C. to 90° C. for 1.5 hours. Themixture was concentrated under reduced pressure and the product oil waspurified by silica gel chromatography (chloroform:methanol, 100;6 aseluting solvents) to give 330 mg of3S-[N-(t-butoxycarbonyl)-N-(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2R-olas a colorless oil (54.5% yield).3S-[N-(t-Butoxycarbonyl)-N-(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2S-ol was also isolated.When purified N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine was used asstarting material, 3S-[N-(t-butoxycarbonyl)-N-(phenylmethyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol was isolated afterpurification by chromatography in an 86% yield.

EXAMPLE 16

Preparation of 3S-(N-t-Butoxycarbonyl)amino-4-phenylbutan-1,2R-diol

To a solution of 1 g (3.39 mmoles) of2S-(N-t-butoxycarbonyl)amino-1S-hydroxy-3-phenylbutanoic acid(commercially available from Nippon Kayaku, Japan) in 50 mL of THF at 0°C. was added 50 mL of borane-THF complex (liquid, 1.0 M in THF), keepingthe temperatures below 5° C. The reaction mixture was warmed to roomtemperature and stirred for 16 hours. The mixture was cooled to 0° C.and 20 mL of water was added slowly to destroy the excess BH₃ and toquench the product mixture, keeping the temperature below 12° C. Thequenched mixture was stirred for 20 minutes and concentrated underreduced pressure. The product mixture was extracted three times with 60mL of ethyl acetate. The organic layers were combined and washed with 20mL of water, 25 mL of saturated sodium chloride solution andconcentrated under reduced pressure to give 1.1 g of crude oil. Thecrude product was purified by silica gel chromatography(chloroform/methanol, 10:6 as eluting solvents) to give 900 mg (94.4%yield) of 3S-(N-t-butoxycarbonyl)amino-4-phenylbutan-1,2R-diol as awhite solid.

EXAMPLE 17

Preparation of 3S-(N-t-Butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-ylToluenesulfonate

To a solution of 744.8 mg (2.65 mmoles) of3S-(N-t-butoxycarbonyl)amino-4-phenylbutan-1,2R-diol in 13 mL ofpyridine at 0° C. was added 914 mg of toluenesulfonyl chloride in oneportion. The mixture was stirred at 0° C. to 5° C. for 5 hours. Amixture of 6.5 mL of ethyl acetate and 15 mL of 5% aqueous sodiumbicarbonate solution was added to the reaction mixture and stirred for 5minutes. The product mixture was extracted three times with 50 mL ofethyl acetate. The organic layers were combined and washed with 15 mL ofwater, 10 mL of saturated sodium chloride solution and concentratedunder reduced pressure to give about 1.1 g of a yellow chunky solid. Thecrude product was purified by silica gel chromatography (ethylacetate/hexane 1:3 as eluting solvents) to give 850 mg (74% yield) of3S-(N-t-butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yltoluenesulfonate as a white solid.

EXAMPLE 18

Preparation of3S-[N-(t-Butoxycarbonyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol

To a solution of 90 mg (0.207 mmoles) of3S-(N-t-butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yltoluenesulfonate in 0.143 mL of isopropanol and 0.5 mL of toluene wasadded 0.103 mL (1.034 mmoles) of isobutylamine. The mixture was warmedto 80 to 85° C. and stirred for 1.5 hours. The product mixture wasconcentrated under reduced pressure at 40 to 50° C. and purified bysilica gel chromatography (chloroform/methanol, 10:1 as elutingsolvents) to give 54.9 mg (76.8% yield) of3S-[N-(t-butoxycarbonyl)amino]-1-(2-methylpropyl)amino-4-phenylbutan-2R-olas a white solid.

EXAMPLE 19

Preparation ofN-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylaminePart A:

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1L). The solutionwas washed sequentially with 1M potassium hydrogen sulfate, saturatedsodium bicarbonate and then saturated sodium chloride solutions. Afterdrying over anhydrous magnesium sulfate and filtering, the solution wasremoved under reduced pressure. To the resulting oil was added hexane(approx. 1L) and the mixture warmed to 60° C. with swirling. Aftercooling to room temperature, the solids were collected and washed with2L of hexane. The resulting solid was recrystallized from hot ethylacetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH+298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (100 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2=mol, 20 equiv.) in 10 mL of isopropyl alcoholwas heated to reflux for 1.5 hours. The solution was cooled to roomtemperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺ m/z=371.

EXAMPLE 20

Preparation ofN-[(1,1-dimethylethoxyl)carbonyl]-N-[2-methylpropyl]-3S-[N¹-(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutylamine

To a solution of 7.51 g (20.3 mmol) ofN-[3S-[(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutyl]-2-methylpropylaminein 67 mL of anhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) oftriethylamine. After cooling to 0° C., 4.4 g (20.3 mmol) ofdi-tert-butyldicarbonate was added and stirring continued at roomtemperature for 21 hours. The volatiles were removed in vacuo, ethylacetate added, then washed with 5% citric acid, saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 9.6 g of crude product Chromatography on silicagel using 30% ethyl acetate/hexane afforded 8.2 g of pureN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane,mass spectum m/e=477 (M+Li).

EXAMPLE 21

Preparation of2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3[N¹-(3-methyl-butyl)-N¹-(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidePart A:

To a solution of N-CBZ-L-tert-leucine (450 mg, 1.7 mmol) andN-hydroxybenzotriazole (260 mg, 1.7 mmol) in DMF (10 mL) was added EDC(307 mg, 1.6 mmol). The solution was stirred for 60 minutes at roomtemperature and then2R-hydroxy-3-[N-(3-methylbutyl)-N-(phenylsulfonyl)amino]-1S-(phenylmethyl)propylamine(585 mg, 1.5 mmol) in DMF (2 mL) was added. The reaction was stirred for16 hours at room temperature, then poured into a 50% saturated solutionof sodium bicarbonate (200 mL). The aqueous mixture was extracted thricewith ethyl acetate (50 mL). The combined ethyl acetate layers werewashed with water (50 mL) and saturated NaCl solution (50 mL), thendried over magnesium sulfate. Filtration and concentration produced anoil which was chromatographed on silica gel (50 gm) eluting with 20%ethyl acetate in hexane. The phenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a solid Anal. Calcd for C₃₅H₄₇N₃O₆S: C, 65.91; H, 7.43;N, 6.59. Found: C, 65.42; H, 7.24; N, 6.55.

Part B:

A solution of phenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(200 mg, 0.31 mmol) in methanol (15 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

Part C:

The resulting free amine from part B (150 mg, 0.3 mmol) was combinedwith diisopropylethylamine (114 uL, 0.33 mmol) in dichloromethane (5mL). To this was added bromoacetyl chloride (27 uL, 0.33 mmol) dropwise.The reaction was stirred for 30 minutes at room temperature, thendiluted with dichloromethane (30 mL) and extracted with 1 N HCl, water,and then saturated NaCl solution (25 mL each). The organic solution wasdried over MgSO₄ and concentrated to a solid. The2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidewas sufficiently pure for use in the next step. This material can alsobe prepared by substituing bromoacetic anhydride for bromoacetylchloride, or one can use chloroacetyl chloride or chloracetic anhydride.

EXAMPLE 22

Preparation of2S-[chloroacetylamino]-N-[2R-hydroxy-3-[N¹-(2-methylpropyl)-N¹-(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamidePart A:

To a solution of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propylamine (1.70 g, 4.18 mmol) in 40 mL of dichloromethane was addedN-carbobenzyloxy-L-isoleucine-N-hydroxysuccinamide ester (1.51 g, 418mmol) and the solution stirred under nitrogen atmosphere for 16 hours.The contents were concentrated in vacuo and the residue was redissolvedin ethyl acetate. The ethyl acetate solution was washed with an aqueoussolution of 5% KHSO₄, saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered, and concentrated toyield 2.47 g of crude product. The product was purified by silica gelchromatography using 12:1 hexane:ethyl acetate eluant to yield 2.3 g.(84% yield) of2S-[(carbobenzyloxy)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide.

Part B:

(1.18 g, 1.8 mmol) of the product from Part A was dissolved in 50 mL ofmethanol, and to this was added 250 mg of 10% Palladium on Carbon whileunder a stream of nitrogen. The suspension was hydrogenated using 50psig of hydrogen for 20 hours. The contents were purged with nitrogenand filtered through celite, and concentrated in vacuo to yield 935 mgof2S-(amino)-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide,which was used without further purification.

Part C:

(0.935 g, 1.8 mmol) of the amine from Part B was dissolved in 15 mL ofdioxane and to this was added (190 mg, 1.85 mmol) of 4-methylmorpholinefolowed by (0.315 g, 1.8 mmol) of chloroacetic anhydride. The reactionmixture was stirred under nitrogen atmosphere for 3 hours, concentratedin vacuo, and redissolved in ethyl acetate. The ethyl acetate solutionwas washed with 50 mL of 5% agueous KHSO₄, saturated NaHCO₃, andsaturated NaCl solution, dried over MgSO₄, filtered and concentrated toyield 613 mg, (68% yield) of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide,after purification by silica gel chromatography using 1:1 hexane:ethylacetate.

EXAMPLE 23

Preparation of2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminePart A: Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride

To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuranwas added, and the mixture heated at 100° C. for 2 hours. The reactionwas cooled, poured into ice water, extracted with methylene chloride,dried over magnesium sulfate, filtered and concentrated the crudematerial. This was recrystallized from ethyl acetate to afford 2.45 g of5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.

Part B: Preparation of Carbamic acid,2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, phenylmethyl ester

To a solution of 1.11 g (3.0 mmol) of N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 20 mL of anhydrousmethylene chloride, was added 1.3 mL (0.94 g, 9.3 mmol) oftriethylamine. The solution was cooled to 0° C. and 0.66 g of5-(2,3-dihydrobenzofuranyl) sulfonyl chloride was added, stirred for 15minutes at 0° C., then for 2 hour at room temperature. Ethyl acetate wasadded, washed with 5% citric acid, saturated sodium bicarbonate, brine,dried and concentrated to yield 1.62 g of crude material. This wasrecrystallized from diethyl ether to afford 1.17 g of pure carbamicacid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester.

Part C: Preparation of [2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 2.86 g of carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, phenylmethyl ester in 30 mL oftetrahydrofuran was hydrogenated 0.99 g of 10% palladium-on-carbon under50 psig of hydrogen for 16 hours. The catalyst was removed by filtrationand the filtrate concentrated to afford 1.99 g of the desired[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine.

EXAMPLE 24

Preparation of Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

Carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester 0.30 g (0.571 mmol) was added to a well mixed powderof anhydrous copper sulfate (1.20 g) and potassium thiocyanate (1.50 g)followed by dry methanol (6 mL) and the resulting black-brown suspensionwas heated at reflux for 2 hrs. The reaction mixture was filtered andthe filtrate was diluted with water (5 mL) and heated at reflux. Ethanolwas added to the reaction mixture, cooled and filtered. The filtrateupon concentration afforded a residue which was chromatographed (ethylacetate:hexane 80:20) to afford 0.26 g (78%) of the desired compound asa solid.

EXAMPLE 25

Preparation of Carbamic acid,2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl esterMethod 1:

Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, phenylmethyl ester (0.25 g, 0.429 mmol) was added to a solutionof isoamylnitrite (0.116 mL, 0.858 mmol) in dioxane (5 mL) and themixture was heated at 85° C. After the cessation of evolution ofnitrogen, the reaction mixture was concentrated and the residue waspurified by chromatography (hexane:ethyl acetate 5:3) to afford 0.130 g(53%) of the desired product as a solid.

Method 2:

Crude benzothiazole-6-sulfonyl chloride in ethyl acetate (100 mL) wasadded to N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine (1.03 g, 2.78 mmol) followedby N-methylmorpholine (4 mL). After stirring at room temperature for 18hr., the reaction mixture was diluted with ethyl acetate (100 mL),washed with citric acid (5%, 100 mL), sodium bicarbonate (saturated, 100mL) and brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (silica gel, ethyl acetate:hexane 1:1) toafford 0.340 g (23%) of desired product.

EXAMPLE 26

Preparation of Carbamic acid, 2R-hydroxy-3-[[(2-aminobenzothiazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester; and Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-7-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

The carbamic acid, 2R-hydroxy-3-[(3-aminophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, phenylmethyl ester 0.36g (0.685 mmol) was added to a well mixed powder of anhydrous coppersulfate (1.44 g) and potassium thiocyanate (1.80 g) followed by drymethanol (10 mL) and the rsulting black-brown suspension was heated atreflux for 2 hrs. The reaction mixture was filtered and the filtrate wasdiluted with water (5 mL) and heated at reflux. Ethanol was added to thereaction mixture, cooled and filtered. The filtrate upon concentrationafforded a rseidue which was chromatographed (ethyl acetate:hexane 1:1)to afford 0.18 g (45%) of the 7-isomer as a solid. Further elution ofthe column with (ethyl acetate:hexane 3:2) afforded 0.80 g (20%)afforded the 5-isomer as a solid.

EXAMPLE 27

Preparation ofN-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylaminePart A: N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol

To a solution of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone(75 g, 0.2 mol) in a mixture of 800 mL of methanol and 800 mL oftetrahydrofuran was added sodium borohydride (13.17 g, 0.348 mol, 1.54equiv.) over 100 min. The solution was stirred at room temperature for 2hours and then concentrated in vacuo. The residue was dissolved in 1000mL of ethyl acetate and washed with 1N KHSO₄, saturated aqueous NaHCO₃,saturated aqueous NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give an oil. The crude product was dissolved in1000 mL of hexanes at 60° C. and allowed to cool to room temperaturewhere upon crystals formed that were isolated by filtration and washedwith copious amounts of hexanes. This solid was then recrystallized fromhot ethyl acetate and hexanes to provide 32.3 g 43% ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C., FAB MS: MLi⁺=340.

Part B: 3(S)-[N-(benzyloxycarbonyl)amino]-1,2(S)-epoxy-4-phenylbutane

A solution of potassium hydroxide (6.52 g. 0.116 mol, 1.2 equiv.) in 970mL of absolute ethanol was treated withN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g,0.097 mol). This solution was stirred at room temperature for 15 minutesand then concentrated in vacuo to give a white solid. The solid wasdissovled in dichloromethane and washed with water, dried over anhydMgSO₄, filetered and concentrated in vacuo to give a white solid. Thesolid was crystallized from hexanes and ethyl acetate to give 22.3 g,77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane,mp 102-103° C., FAB MS: MH⁺=298.

Part C:N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine

A solution of N-benzylcarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenyl butane(50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents)in 650 mL of isopropyl alcohol was heated to reflux for 1.25 hours. Thesolution was cooled to room temperature, concentrated in vacuo and thenpoured into 1 L of stirring hexane whereupon the product crystallizedfrom solution. The product was isolated by filtration and air dried togive 57.56 g, 92% ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]-N-isobutylamine, mp108.0-109.5° C., MH+ m/z=371.

EXAMPLE 28

Preparation of 1,3-benzodioxole-5-sulfonyl chlorideMethod 1:

To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 7.84 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxole wasadded, and the mixture heated at 100° C. for 2 hours. The reaction wascooled, poured into ice water, extracted with methylene chloride, driedover magnesium sulfate, filtered and concentrated to give 7.32 g ofcrude material as a black oil. This was chromatographed on silica gelusing 20% methylene chloride/hexane to afford 1.9 g of(1,3-benzodioxol-5-yl)sulfonyl chloride.

Method 2:

To a 22 liter round bottom flask fitted with a mechanical stirrer, acooling condenser, a heating mantle and a pressure equalizing droppingfunnel was added sulfur trioxide DMF complex (2778 g, 18.1 moles).Dichloroethane (4 liters) was then added and stirring initiated.1,3-Benzodioxole (1905 g, 15.6 moles) as then added through the droppingfunnel over a five minute period. The temperature was then raised to 75°C. and held for 22 hours (NMR indicated that the reaction was done after9 hours.) The reaction was cooled to 26° and oxalyl chloride (2290 g,18.1 moles) was added at a rate so as to maintain the temperature below40° C. (1.5 hours). The mixture was heated to 67° C. for 5 hoursfollowed by cooling to 16° C. with an ice bath. The reaction wasquenched with water (51) at a rate which kept the temperature below 20°C. After the addition of water was complete, the mixture was stirred for10 minutes. The layers were separated and the organic layer was washedagain twice with water (51). The organic layer was dried with magnesiumsulfate (500 g) and filtered to remove the drying agent. The solvent wasremoved under vacuum at 50° C. The resulting warm liquid was allowed tocool at which time a solid began to form. After one hour, the solid waswashed with hexane (400 mL), filtered and dried to provide the desiredsulfonyl chloride (2823 g). The hexane wash was concentrated and theresulting solid washed with 400 mL hexane to provide additional sulfonylchloride (464 g). The total yield was 3287 g (95.5% based upon1,3-benzodioxole).

Method 3:

1,4-benzodioxan-6-sulfonyl chloride was prepared according to theprocedure disclosed in EP 583960, incorporated herein by reference.

EXAMPLE 29

Preparation of1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanolMethod 1:

To a 5000 mL, 3-necked flask fitted with a mechanical stirrer was addedN-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine-oxalicacid salt (354.7 g, 0.7 mole) and 1,4-dioxane (2000 mL). A solution ofpotassium carbonate (241.9 g, 1.75 moles) in water (250 mL) was thenadded. The resultant heterogeneous mixture was stirred for 2 hours atroom temperature followed by the addition of 1,3-benzodioxole-5-sulfonylchloride (162.2 g, 0.735 mole) dissolved in 1,4-dioxane (250 mL) over 15minutes. The reaction mixture was stirred at room temperature for 18hours. Ethyl acetate (1000 mL) and water (500 mL) were charged to thereactor and stirring continued for another 1 hour. The aqueous layer wasseparated and further extracted with ethyl acetate (200 mL). Thecombined ethyl acetate layers were washed with 25% brine solution (500mL) and dried over anhydrous magnesium sulfate. After filtering andwashing the magnesium sulfate with ethyl acetate (200 mL), the solventin the filtrate was removed under reduced pressure yielding the desiredsulfonamide as an viscous yellow foamy oil (440.2 g 105% yield). HPLC/MS(electrospray) (m/z 601 [M+H]⁺].

EXAMPLE 30

Preparation of1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-amino-4-phenyl-2(R)-butanol.methanesulfonicacid saltMethod 1:

Crude1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanol(6.2 g, 0.010 moles) was dissolved in methanol (40 mL). Methanesulfonicacid (0.969 g, 0.010 moles) and water (5 mL) were then added to thesolution. The mixture was placed in a 500 mL Parr hydrogenation bottlecontaining 20% Pd(OH)₂ on carbon (255 mg, 50% water content). The bottlewas placed in the hydrogenator and purged 5 times with nitrogen and 5times with hydrogen. The reaction was allowed to proceed at 35° C. with63 PSI hydrogen pressure for 18 hours. Additional catalyst (125 mg) wasadded and, after purging, the hydrogenation continued for and additional20 hours. The mixture was filtered through celite which was washed withmethanol (2×10 mL). Approximately one third of the methanol was removedunder reduced pressure. The remaining methanol was removed by aziotropicdistillation with toluene at 80 torr. Toluene was added in 15, 10, 10and 10 mL portions. The product crystallized from the mixture and wasfiltered and washed twice with 10 mL portions of toluene. The solid wasdried at room temperature at 1 torr for 6 hours to yield the amine salt(4.5 g, 84%). HPLC/MS (electrospray) was consistent with the desiredproduct (m/z 421 [M+H]⁺).

Method 2:

Part A:N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.oxalicacid salt (2800 g, 5.53 moles) and THF (4L) were added to a 22L roundbottom flask fitted with a mechanical stirrer. Potassium carbonate (1921g, 13.9 moles) was dissolved in water (2.8L) and added to the THFslurry. The mixture was then stirred for one hour.1,3-benzodioxole-5-sulfonyl chloride (1281 g, 5.8 moles) was dissolvedin THF (1.4L) and added to the reaction mixture over 25 minutes. Anadditional 200 mL of THF was used to rinse the addition funnel. Thereaction was allowed to stir for 14 hours and then water (4 L) wasadded. This mixture was stirred for 30 minutes and the layers allowed toseparate. The layers was removed and the aqueous layer washed twice withTHF (500 mL). The combined THF layers were dried with magnesium sulfate(500 g) for one hour. This solution was then filtered to remove thedrying agent and used in subsequent reactions.

Part B: To the THF solution of crude1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanolwas added water (500 mL) followed by methane sulfonic acid (531 g, 5.5moles). The solution was stirred to insure complete mixing and added toa 5 gallon autoclave. Pearlman's catalyst (200 g of 20% Pd(OH)₂ on C/50%water) was added to the autoclave with the aid of THF (500 mL). Thereactor was purged four times with nitrogen and four times withhydrogen. The reactor was charged with 60 psig of hydrogen and stirringat 450 rpm started. After 16 hours, HPLC analysis indicated that a smallamount of the mono-benzyl intermediate was still present. Additionalcatalyst (50 g) was added and the reaction was allowed to run overnight.The solution was then filtered through celite (500 g) to remove thecatalyst and concentrated under vacuum in five portions. To eachportion, toluene (500 mL) was added and removed under vacuum toazeotropically removed residual water. The resulting solid was dividedinto three portions and each washed with methyl t-butyl ether (2 L) andfiltered. The residual solvent was removed at room temperature in avacuum oven at less than 1 torr to yield the 2714 g of the expectedsalt.

If desired, the product can be further purified by the followingprocedure. A total of 500 mL of methanol and 170 g of material fromabove was heated to reflux until it all dissolved. The solution wascooled, 200 mL of isopropanol added and then 1000-1300 mL of hexane,whereupon a white solid precipitated. After cooling to 0° C., thisprecipitate was collected and washed with hexane to afford 123 g of thedesired material. Through this procedure, the original material whichwas a 95:5 mixture of alcohol diastereomers was greater than 99:1 of thedesired diastereomer.

EXAMPLE 31

Preparation of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminePart A: Preparation of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamic acid phenylmethyl ester

To a solution of 3.19 g (8.6 mmol) of N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 40 mL of anhydrousmethylene chloride, was added 0.87 g of triethylamine. The solution wascooled to 0° C. and 1.90 g of (1,3-benzodioxol-5-yl)sulfonyl chloridewas added, stirred for 15 minutes at 0° C., then for 17 hours at roomtemperature. Ethyl acetate was added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried and concentrated to yieldcrude material. This was recrystallized from diethyl ether/hexane toafford 4.77 g of pure2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid phenylmethyl ester.

Part B: Preparation of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 4.11 g of carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester in 45 mL of tetrahydrofuran and 25 mL of methanol washydrogenated over 1.1 g of 10% palladium-on-carbon under 50 psig ofhydrogen f-or 16 hours. The catalyst was removed by filtration and thefiltrate concentrated to afford 1.82 g of the desired2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine.

EXAMPLE 32

Preparation of Benzothiazole-6-sulfonyl ChloridePart A: Preparation of N-(4-Sulfonamidophenyl)thiourea

A mixture of sulfanilamide (86 g, 0.5 mole), ammonium thiocyanate (76.0g, 0.5 mole) and dilute hydrochloric acid (1.5 N, 1 L) was mechanicallystirred and heated at reflux for 2 hr. About 200 mL of water wasdistilled off and concentration of the reaction mixture afforded asolid. The solid was filtered and was washed with cold water and airdried to afford 67.5 g (59%) of the desired product as a white powder.

Part B: Preparation of 2-Amino-6-sulfonamidobenzothiazole

Bromine (43.20 g, 0.27 mol) in chloroform (200 mL) was added over 1 hr.to a suspension of N-(4-sulfonamidophenyl)-thiourea (27.72, 0.120 mol)in chloroform (800 mL). After the addition, the reaction mixture washeated at reflux for 4.5 hr. The chloroform was removed in vacuo and theresidue was repeatedly distilled with additional amounts of chloroform.The solid obtained was treated with water (600 mL) followed by ammoniumhydroxide (to make it basic), then was heated at reflux for 1 hr. Thecooled reaction mixture was filtered, washed with water and air dried toafford 22.0 g (80%) of the desired product as a white powder.

Part C: Preparation of Benzothiazole-6-sulfonic acid

A suspension of 2-amino-6-sulfonamido-benzothiazole (10.0 g, 43.67 mmol)in dioxane (300 mL) was heated at reflux. Isoamylnitrite (24 mL) wasadded in two portions to the reaction mixture. Vigorous evolution of gaswas observed (the reaction was conducted behind a shield as aprecaution) and after 2 hr., a red precipitate was deposited in thereaction vessel. The reaction mixture was filtered hot, and the solidwas washed with dioxane and was dried. The solid was recrystallized frommethanol-water. A small amount of a precipitate was formed after 2 days.The precipitate was filtered off and the mother liquor was concentratedin vacuo to afford a pale red-orange solid (8.0 g, 85%) of pure product.

Part D: Preparation of 6-Chlorosulfonylbenzothiazole

Thionyl chloride (4 mL) was added to a suspension of thebenzothiazole-6-sulfonic acid (0.60 g, 2.79 mmol) in dichloroethane (15mL) and the reaction mixture was heated at reflux and dimethylformamide(5 mL) was added to the reaction mixture to yield a clear solution.After 1.5 hr. at reflux, the solvent was removed in vacuo and excess HCland thionyl chloride was chased by evaporation with dichloroethane.

EXAMPLE 33

Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamidePart A: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3,3-dimethylbutanamide

To a solution of 118.8 g (0.776 mol) of N-hydroxybenzotriazole and 137.1g (0.52 mol) of N-carbobenzyloxycarbonyl-L-tert-leucine in 750 mL ofanhydrous DMF at 0° C. under a nitrogen atmosphere, was added 109.1 g(0.57 mol) of EDC. After stirring at 0° C. for 2 hours, a solution of273 g (0.53 mol) of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminemethanesulfonate, previously neutralized with 228 mL (210 g, 2.08 mol)of 4-methylmorpholine, in 250 mL of anhydrous DMF was added. Afterstirring at 0° C. for 30 minutes, the mixture stirred at roomtemperature for 18 hours. The solvents were removed under reducedpressure at 45° C., 1.5 L of ethyl acetate added, washed with 5% citricacid, saturated sodium bicabonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 400 g of crude material.This was chromatographed in 3 batches on a Prep 2000 Chromatogram onsilica gel using 20%-50% ethyl acetate/hexane as eluent to yield 320 gof purified material, m/e=674 (M+Li), 98% by HPLC.Part B: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide

A solution of 312 g of the Cbz compound from above in 1L oftetrahydrofuran was hydrogenated in the presence of 100 g of 4%palladium-on-carbon catalyst under 60 psig of hydrogen for 6 hours atroom temperature. The catalyst was removed by filtration and thesolvents removed under reduced pressure to afford 240 g of the desiredcompound.Part C: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

To a solution of 234.3 g (0.439 mol) of the amine from above in 1L ofmethylene chloride, was added 80 mL (595 g, 0.46 mol) ofdiisopropylethylamine, followed by the slow addition at room temperatureof 78.8 g (0.46 mol) of chloroacetic anhydride while maintaining thetemperature below 35° C. After stirring for an additional 1 hour,analysis by HPLC indicated a small amount of starting material was stillpresent, and 1.5 g of chloroacetic anhydride was added. After 10minutes, the solvents were removed under reduced pressure, 1 L ethylacetate added, washed with 5% citric acid, saturated sodium bicarbonate,brine, dried over anhydrous magnesium sulfate, filtered and concentratedto yield 314 g of crude material. This was chromatographeed in 3portions on a Prep 2000 Chromatogram on silica gel using 20-50% ethylacetate/hexane to afford 165 g of the desired compound, m/e=616 (M+Li),98% by HPLC.

EXAMPLE 34

Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3S-methylpentanamidePart A: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3S-methylpentanamide

To a cooled solution of N-t-Boc-L-isoleucine 2.02 g (8.74 mmol) and 2.00g (13.11 mmol) of N-hydroxybenzotriazole in 17 mL ofN,N-dimethylformamide was added 1.84 g (9.61 mmol) of EDC and stirred at0° C. for one hour. To this was added a solution of 3.67 g (8.74 mmol)of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl amine in 6 mL of N,N-dimethylformamideand the solution stirred for 16 hours. The solvent was removed in vacuo,replaced with ethyl acetate, and washed with saturated sodiumbicarbonate, 5% citric acid and brine. The organic layers were driedover magnesium sulfate, filtered and concentrated to yield 6.1 grams ofcrude product, which was chromatoraphed on silica gel using 1:1 ethylacetate:hexane eluant to produce 4.3 g (78% yield) ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3S-methylpentanamide.Part B: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloridesalt

N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3S-methylpentanamide(4.29 g, 6.77 mmol) was dissolved in 20 mL of 4N HCl in dioxane andstirred for 20 minutes. The precipitated product was stripped two timesfrom diethyl ether and the crude hydrochloride salt was used insubsequent reactions.Part C: Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3S-methylpentanamide

N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloridesalt (3.62 g, 6.77 mmol) was dissolved in 45 mL of methylene chlorideand to this was added 1.3 g (10.15 mmol) of N,N-diisopropylethyl amineto neutrallize the salt, and another 0.923 g (7.10 mmol) ofdiisopropylethyl amine followed by 1.22 g (7.11 mmol) of chloroaceticanhydride. The solution was stirred at room temperature for 30 minutes.The contents were concentrated on a rotory evaporator and the residuewas partitioned between ethyl acetate and water. The organic layer waswashed with 5% citric acid and then saturated sodium bicarbonate andbrine. The organic layers were dried over magnesium sulfate filtered andconcentrated to yield 4.12 g of crude product. Recrystallization fromethyl acetate hexane yielded 3.5 g (85% yield) ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3S-methylpentanamide,as a white solid; mass spectrum m/z=616 (M+Li).

EXAMPLE 35

Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-methylbutaneamidePart A: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3-methylbutaneamide

A 250 mL round bottom flask equipped with magnetic stir bar was chargedwith N-Cbz-L-Valine (4.22 g, 16.8 mmol) in 20 mL DMF. The solution wascooled to 0° C. and charged with HoBt (2.96, 21.9 mmol) and EDC (3.22 g,16.8 mmol) and stirred 1 hour. The reaction was then charged withN-methylmorpholine (1.7 g, 16.8 mmol),2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine(7.55 g, 14.6 mmol) in 30 mL of DMF. The reaction was stirred overnightat room temperature then concentrated in vacuo and partioned betweenethyl acetate and 5% Citric acid. The combined organic layers werewashed with saturated sodium bicarbonate and brine, and dried oversodium sulfate. Concentration in vacuo yielded 10 g crude product.Purification by Prep HPLC (20-40% ethyl acetate/hexane) yielded 5.8 g(61%) of the desired compound.Part B Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-methylbutaneamide

A 300 mL Fisher-Porter vessel equipped with magnetic stir bar wascharged withN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3-methylbutaneamide(5.8 g), 2.3 g of 10% Pd-C in 75 mL tetrahydrofuran. The reaction wascharged with 50 psi H₂ and hydrogenated overnight. The reaction mixturewas filtered thru Celite and concentrated in vacuo to yield 4.4 g ofwhite foam that was used in subsequent reactions without furthurpurification.Part C: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-methylbutaneamide

A 250 mL round bottom flask equipped with magnetic stir bar was chargedwith crudeN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-methylbutaneamide(4.35 g) in 60 mL CH₂Cl₂. The reaction was charged with 1.19 gdiisopropylamine followed by 1.5 g of chloroacetic anhydride and stirreduntil TLC indicated no remaining starting material (about 1.5 hours).The reaction was concentrated in vacuo and partioned between ethylacetate and saturated sodium bicarbonate. The combined organic layerswere washed with brine, and dried over sodium sulfate. Concentration invacuo yielded 5.17 g of desired product that was used in subsequentreactions without furthur purification.

EXAMPLE 36

Preparation of N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-(methylsulfonyl)propaneamidePart A: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(methylthio)propaneamide

N-t-Boc-S-methyl-(L)-cysteine (2.80 g, 11.9 mmol),1-Hydroxybenzotriazole hydrate (1.92 g, 12.5 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.27 g,11.9 mmol) were mixed in N,N-dimethylformamide (30.0 mL) at 0° C. for 10min. N-Methylmorpholine (3.03 g, 33.0 mmol) was added and the solutionstirred an additional 10 min at 0° C.2R-Hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine(5.00 g, 11.9 mmol) was added and the solution was warmed to roomtemperature and stirred for 2 hours. The reaction mixture was pouredinto ethyl acetate (500 mL) and washed with 10% aqueous hydrochloricacid (3×100 mL), saturated aqueous sodium bicarbonate (3×100 mL) andbrine (2×100 mL). The organic layer was dried over sodium sulfate andpercolated through a bed of silica gel (50 g). The desired product (7.13g, 11.19 mmol, 93% yield) was obtained as a white solid by removal ofthe solvent at reduced pressure; m/e calcd 637; found (M+Li) 644.Part B: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(methylsulfonyl)propaneamide

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(methylthio)propaneamide(7.10 g, 11.1 mmol) was dissolved in methanol (150 mL). A solution ofoxone® (20.8 g, 33.9 mmol) in water (150 mL) was added dropwise to thesolution at room temperature over 1.5 hours. The solution became cloudyand a precipitate formed during the addition The reaction was stirredfor an additional 1 hour and tetrahydrofuran (200 mL) was added. Afteran additional 1 hour of mixing the solution was poured into ethylacetate (1000 mL) and washed with water (3×200 mL) followed by brine(2×300 ml). The organic layer was dried over anhydrous sodium sulfateand solvent removed at reduced pressure. The desired product (5.75 g,8.86 mmol, 79% yield) was obtained as an off white solid; m/e calcd 669;found (M+H) 670.Part C: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-(methylsulfonyl)propaneamide.hydrochloride salt

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(methylsulfonyl)propaneamide (5.5 g, 8.20 mmol) was dissolved in dichloromethane (100mL) at room temperature. Anhydrous hydrochloric acid was bubbled throughthe solution for 15 min. The solution was stirred at room temperaturefor 2 hours and the solvent was removed at reduced pressure. The desiredproduct (4.91 g, 8.10 mmol, 99% yield) was obtained as a white solid;m/e calcd 569; found (M+Li) 576.Part D: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-(methylsulfonyl)propaneamide

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-(methylsulfonyl)propaneamide.hydrochloridesalt (4.00 g, 6.59 mmole) was mixed at room temperature in acetonitrile(40 mL). Triethylamine (2.10 g, 21.0 mmol) and chloroacetic anhydride(1.12 g, 6.59 mmol) were added. The solution was stirred at roomtemperature for 16 hours and poured into ethyl acetate (250 mL). Thesolution was washed with 10% aqueous acetic acid (2×100 mL), saturatedaqueous sodium bicarbonate (2×100 mL), and brine (2×100 mL). The organiclayer was dried over anhydrous sodium sulfate and solvent removed atreduced pressure. The product (1.20 g, 1.85 mmol, 28% yield) wasobtained as a white solid by crystallization from ethyl acetate andhexanes; m/e calcd 645; found (M+Li) 652.

EXAMPLE 37

Preparation of N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-methyl-3-(methylsulfonyl)butaneamidePart A: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-3-(methylthio)butaneamide

The N-t-boc-S-methyl-L-penicillamine dicyclohexylamine salt (4.00 g,9.00 mmol), 1-Hydroxybenzotriazole hydrate (1.69 g, 11.00 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g,9.00 mmol) were mixed in dimethylformamide (60.0 mL) at roomtemperature. The heterogeneous mixture was stirred for 1 hour and2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl)](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine(3.78 g, 9.00 mmol) was added and the heterogenous mixture was stirredfor 16 hours. The solution was poured into ethyl acetate (600 mL) andwashed with 10% aqueous acetic acid (2×300 mL), saturated aqueous sodiumbicarbonate (2×300 mL) and brine (300 mL). The solution was dried oversodium sulfate and the solvent was removed in vacuo. The desired productwas purified by flash chromatography (0-80% ethyl acetate/hexanes onsilica gel). The product (5.21 g, 7.83 mmol, 87% yield) was obtained asa white foam; m/e calcd 665; found (M+Li) 672.Part B: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-3-(methylsulfonyl)butaneamide

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-3-(methylthio)butaneamide(5.01 g, 7.53 mmol) was dissolved in tetrahydrofuran (250 ml). Asolution of oxone® (13.8 g, 22.6 mmol) in water (250 mL) was addeddropwise to the solution at room temperature over 2 hours. The solutionbecame cloudy and a precipitate formed during the addition. The solutionwas poured into ethyl acetate (500 mL) and washed with water (3×200 mL)followed by brine (2×300 mL). The organic layer was dried over anhydroussodium sulfate and solvent removed in vacuo. The product (4.72 g, 6.77mmol, 89% yield) was obtained as a white foam; m/e calcd 697; found(M+Li) 704.Part C: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-methyl-3-(methylsulfonyl)butaneamide.hydrochloridesalt

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-3-(methylsulfonyl)butaneamide(4.51 g, 6.46 mmol) was dissolved in dichloromethane (200 mL) at roomtemperature. Anhydrous hydrochloric acid was bubbled through thesolution for 30 min. The solution was stirred at room temperature for 1hour and the solvent was removed in vacuo. The product (4.02 g, 6.35mmol, 99% yield) was obtained as a white solid; m/e calcd 697; found(M+Li) 704.Part D: Preparation ofN-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3-methyl-3-(methylsulfonyl)butaneamide

N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3-methyl-3-(methylsulfonyl)butaneamide.hydrochloridesalt (3.90 g, 6.15 mmole) was mixed at room temperature in acetonitrile(40 mL). Triethylamine (1.86 g, 18.45 mmol) and chloroacetic anhydride(1.05 g, 6.15 mmol) were added. The solution was stirred at roomtemperature for 16 hours and poured into ethyl acetate (250 mL). Thesolution was washed with 10% aqueous acetic acid (2×100 mL), saturatedaqueous sodium bicarbonate (2×100 mL), and brine (2×100 mL). The organiclayer was dried over anhydrous sodium sulfate and solvent was removed invacuo. A yellow oil (4.3 g) was obtained and purified by flashchromatography (silica gel, 50-75% ethyl acetates in hexanes. Theproduct (2.15 g, 3.18 mmol, 52% Yield) was obtained as a white foam; m/ecalcd 674; found (M+Li) 681.

EXAMPLE 38

Preparation of N-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamidePart A: Preparation ofN-[(1,1-dimethylethoxyl)carbonyl]-N-[2-methylpropyl]-3S-[N¹-(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutylamine

A solution ofN-[3S-[N¹-(benzyloxycarbonyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)amine(18.5 g, 50 mmol), BOC-ON (12.35 g, 50 mmol) and triethylamine (7 mL) intetrahydrofuran (400 mL) was stirred at room temperature for 18 hoursand then concentrated in vacuo. The residue was dissolved indichloromethane (1 L) and washed with sodium hydroxide (5%, 2×200 mL)and brine, dried (MgSO₄) and then concentrated in vacuo to afford 23.5 g(quantitative yield) of the pure desired product.Part B: Preparation ofN-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3,3-dimethylbutanamide

N-[(1,1-dimethylethoxyl)carbonyl]-N-[2-methylpropyl]-3S-[N¹-(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutylaminein ethanol was hydrogenated at 45 psig of hydrogen in the presence of 5%pd(C) catalyst to yieldN-[(1,1-dimethylethoxyl)carbonyl]-N-[2-methylpropyl]-3S-[N¹-(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutylamine.Following standard workup, the crude amine (12.24 g, 36.42 mmol) wasadded to a mixture of N-carbobenzyloxycarbonyl-L-tert-leucine (9.67 g,36.42 mmol), HOBT (4.92 g, 36.42 mmol) and EDC (6.98 g, 36.42 mmol) inDMF (300 mL) after the mixture was stirred at room temperature for 1hour. The mixture was stirring for an additional 18 hours. The DMF wasremoved in vacuo, the residue was dissolved in dichloromethane (500 mL),washed with sodium hydroxide (5%, 2×200 mL) and brine (200 mL), driedand concentrated to afford 21 g (quantitative) of the desired product.Part C: Preparation ofN-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide

N-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3,3-dimethylbutanamide(20 g, 34.29 mmol) in methanol (250 mL) was hydrogenated at roomtemperature in the presence of Pd/C (10%, 5 g). The catalyst wasfiltered off and the filtrate was concentrated to afford 13.8 g (90%) ofthe pure desired product.Part D: Preparation ofN-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

ToN-[2R-hydroxy-3-[[(1,1-dimethylethoxy)carbonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide(12.45 g, 27.70 mmol) in dichloromethane (200 mL) was added chloroaceticanhydride (5.21 g, 30.48 mmol) and the reaction mixture was stirred for18 hours. The reaction mixture was washed with citric acid (5%, 100 mL),sodium bicarbonate (saturated, 100 mL) and brine, dried (MgSO₄) andconcentrated to afford 12.0 g (82%) of the pure desired product.

EXAMPLE 39

Preparation of 2R-hydroxy-3-[[(1,4-benzodioxan-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl carbamic acidphenylmethyl ester

To a solution of the N-[3S-[(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)amine (0.5 g, 1.35mmol) in CH₂Cl₂ (5.0 mL) containing Et₃N (0.35 mL, 2.5 mmol) was added1,4-benzodioxan-6-sulfonyl chloride (0.34 g, 1.45 mmol) and stirred at0° C. for 30 min. After stirring at room temperature for 1 hour, thereaction mixture was diluted with CH₂Cl₂ (20 mL), washed with cold 1NHCl (3×20 mL), water (2×20 mL), satd. NaHCO₃ (2×20 mL) and water (3×20mL), dried (Na₂SO₄) and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography using 35% EtOAcin hexane to give the desired product as a white amorphous solid whichcrystallized from MeOH as a white powder (0.65 g. 84% yield): m. p.82-84° C., HRMS-FAB: calcd for C₃₀H₃₇N₂O₇S 569.2321 (MH⁺), found569.2323.

EXAMPLE 40

Preparation of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamidePart A. Preparation of2S-[[(1,1-dimethylethoxy)carbonyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide

To a cooled solution of N-t-Boc-L-propargyl glycine (5.0 g, 23.4 mmol)and 4.7 g (1.5 equiv.) of N-hydroxybenzotriazole in 40 mL ofN,N-dimethylformamide was added 4.6 g (23.4 mmol) of EDC and stirred at0 C for one hour. To this was added a solution of 12.10 g (23.4 mmol) of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 6 mL of N,N-dimethylformamide and the solution stirred for 16 hours.The solvent was removed by rotory evaporation, replaced with ehtylacetate, and washed with saturated sodium bicarbonate, 5% citric acidand brine. The organics were dried over magnesium sulfate, filtered andconcentrated to yield 13.3 grams of crude product, which wascrystallized from diethyl ether: ethyl acetate to yield 6.9 g of2S-[[(1,1-dimethylethoxy)carbonyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide.Part B. Preparation of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide

5.0 g (8.12 mmol) of the product from Part A, was dissolved in 20 mL of4N HCl in dioxane and stirred for 30 minutes. The precipitated productwas stripped two times from diethyl ether and this crude hydrochloridesalt was used in Part C.Part C. Preparation of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamide

4.4 g (8.12 mmol) of amine hydrochloride from Part B was dissolved in 60mL of methylene chloride and to this was added 3.0 g (24 mmol) ofN,N-diisopropylethyl amine, followed by 1.38 g (8.1 mmol) ofchloroacetic anhydride. The solution was stirred at room temperatureovernight. The contents were concentrated on a rotory evaporator and theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with 5% citric acid and then saturated sodiumbicarbonate and brine. The organics were dried over magnesium sulfatefiltered and concentrated to yield 4.3 g of crude product.Recrystallization from ethyl acetate hexane yielded 3.6 g (75% yield) of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]pent-4-ynamideas a white solid.

EXAMPLE 41

Preparation of2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminePart A: Preparation of2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid phenylmethyl ester

To a solution of 4.0 g (10.8 mmol) of N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 50 mL of anhydrousmethylene chloride, was added 4.5 mL (3.27 g, 32.4 mmol) oftriethylamine. The solution was cooled to 0° C. and 2.63 g (11.9 mmol)of 4-nitrobenzene sulfonyl chloride was added, stirred for 30 minutes at0° C., then for 1 hour at room temperature. Ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, driedand concentrated to yield 5.9 g of crude material. This wasrecrystallized from ethyl acetate/hexane to afford 4.7 g of pure[2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid phenylmethyl ester, m/e=556 (M+H).

Part B: Preparation of 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl) propylamine

A solution of 3.0 g (5.4 mmol) of2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid phenylmethyl ester in 20 mL of ethyl acetate was hydrogenated over1.5 g of 10% palladium-on-carbon catalyst under 35 psig of hydrogen for3.5 hours. The catalyst was removed by filtration and the solutionconcentrated to afford 2.05 g of the desired2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,m/e=392(M+H).

EXAMPLE 42

Preparation of2S-[[(N-methylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

To 6.55 g (10.7 mmol) ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamidewas added 25 mL of tetrahydrofuran, the solvent removed under reducedpressure to remove any ethyl acetate, and then 25 mL of tetrahydrofuranwas added. To this solution at 10° C. was added 19 mL (214 mmol) of 40%aqueous methylamine. After 2 hours, the solvents were removed underreduced pressure, added 1 L ethyl acetate, washed with saturated sodiumbicarbonate, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated to afford 6.0 g of crude material, which was assayed byHPLC to be 98% purity.

EXAMPLE 43

Preparation ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(N-methylamino)acetyl]amino]-3S-methylpentanamide

To 3.47 g (5.7 mmol) ofN-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3S-methylpentanamidewas added 50 mL of tetrahydrofuran. To this solution was added 12 mL(135 mmol) of 40% aqueous methylamine. After 6 hours, the solvents wereremoved under reduced pressure, added ethyl acetate, washed withsaturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 3.5 g of crude material,which was assayed by HPLC to be 96% purity. The product waschromatographically purified on basic alumina using methanol and ethylacetate eluants to yield 2.88 g (85%) pure desired product (100% byHPLC); m/e C₃₀H₄₄N₄O₇S calcd 604.77; found (M+Li) 611.

EXAMPLE 44

Preparation of2S-[[N-(2-hydroxyethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 2.0 g2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamideand 4.0 g 2-hydroxyethyl amine (20 eq.) in 8 mL tetrahydrofuran wasstirred 6 hours at room temperature. The reaction was concentrated invacuo and partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The combined organics were washed with brine, dried, andconcentrated in vacuo to the crude free base. The product was dissolvedin 25 mL acetonitrile and 2.0 eq. aqueous HCl was added. After 10minutes the reaction was concentrated in vacuo and chased with 30 mlwater and vacumn dried over P₂O₅.

EXAMPLE 45

Preparation of2S-[[N-(2-methoxyethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 2.0 g of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamideand 4.8 mL 2-methoxyethyl amine (20 eq.) in 8 mL tetrahydrofuran wasstirred 4 hours at room temperature. The reaction was concentrated invacuo and partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The combined organics were washed with brine, dried, andconcentrated in vacuo to the crude free base. The product was taken upin 25 mL acetonitrile and 2.0 eq. aqueous HCl was added. After 10minutes the reaction was concentrated in vacuo and chased with 30 mlwater and vacumn dried over P₂O₅.

EXAMPLE 46

Preparation of2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 2.0 g of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamideand 4.5 mL cyclopropyl amine (20 eq.) in 8 mL tetrahydrofuran wasstirred 24 hours at room temperature. The reaction was concentrated invacuo and partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The combined organics were washed with brine, dried, andconcentrated in vacuo to the crude free base. The product was taken upin 25 mL acetonitrile and 2.0 eq. aqueous HCl was added. After 10minutes the reaction was concentrated in vacuo and chased with 30 mlwater and vacumn dried over P₂O₅ to yield 1.5 g white solid.

EXAMPLE 47

Preparation of 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole

A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026 mole) inchlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30 minutes andat room temperature for 3 hours. The resulting dark colored reactionmixture was poured into an ice-water mixture (200 mL), and stirred atroom temperature for 30 minutes. The resulting precipitate was filteredand washed with cold water (500 mL). The solid was dried overnight underhigh vacuum in a desiccator over NaOH pellets to give5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as agrey powder. ¹H NMR (DMSO-d₆) d: 3.89 (s, 3H), 7.55 (d, J=8.4 Hz, 1H),7.65 (d, J=8.4 Hz, 1H), 7.88 (s, 1H). (German Patent DE 3826036)

EXAMPLE 48

Preparation ofN-[2R-hydroxy-3-[N¹-[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl]-N¹-(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]carbamicacid phenylmethyl ester

To a cold solution of N-[3S-[(phenylmethoxycarbonyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)amine (5.0 g, 13.5mmol) in dichloromethane (70 mL) was added triethylamine (5.95 g, 54.0mmol) followed by the addition of5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (4.29 g, 14.85 mmol)in small portions as a solid. The reaction mixture was stirred at 0° C.for 30 minutes and at room temperature for 2.5 hours when reaction ofthe amino alcohol was complete. The mixture was cooled and filtered, andthe filtrate was concentrated. The resulting residue was dissolved inEtOAc (200 mL), washed successively with cold 5% citric acid (3×50 mL),saturated aqueous sodium bicarbonate (3×50 mL) and water (3×100 mL),then dried (Na₂SO₄), concentrated and dried under vacuum. The residuewas triturated with methanol, cooled, filtered, washed with MeOH-EtOAc(1:1, v/v) and dried in a desiccator to give pureN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)-amino]-1S-(phenylmethyl)propyl]carbamic acid phenylmethyl ester (6.02 g, 72%) as a light brownpowder: FABMS: m/z=630 (M+Li); HRMS: calcd. for C₃₁H₃₈N₅O₇S (M+H)624.2492, found 624.2488.

EXAMPLE 49

Preparation of 2R-hydroxy-3-[[(2-amino-benzimidazol-5-yl)sulfonyl](2-methyl-propyl)amino]-1S-(phenylmethyl) propylamine

A solution ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]carbamicacid phenylmethyl ester (0.36 g, 0.58 mmol) in 2.5 N methanolic KOH(2.00 mL) was heated at 70° C. under a nitrogen atmosphere for 3 hours.The reaction mixture was diluted with water (10 mL) and extracted withEtOAc (3×15 mL). The combined organic extracts were washed with brine,dried (Na₂SO₄) and concentrated. The resulting residue was purified byreverse-phase HPLC using a 10-90% CH₃CN/H₂O gradient (30 min) at a flowrate of 70 mL/min. The appropriate fractions were combined and freezedried to give pure2R-hydroxy-3-[[(2-amino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenyl-methyl)propylamine(0.22 g, 58%) as a white powder: FAB-MS m/z=432 (M+H); HRMS: calcd. forC₂₁H₃₀N₅O₃S (M+H) 432.2069, found 432.2071.

EXAMPLE 50

Preparation ofN-[2R-hydroxy-3-[[(2-amino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)-amino]-1S-(phenylmethyl)propyl]carbamic acid phenylmethyl ester

To a solution of2R-hydroxy-3-[[(2-amino-benzimidazol-5-yl)sulfonyl](2-methyl-propyl)amino]-1S-(phenylmethyl)propylamine (0.22 g, 0.33 mmol) in THF (3.00 mL), triethylamine (0.11 g,1.1 mmol) and benzyloxycarbonyl succinimide (0.09 g, 0.36 mmol) wereadded, and the reaction mixture was stirred at room temperature for 16hours. The solution was concentrated, and the residue was partitionedbetween EtOAc (15 mL) and saturated aqueous sodium bicarbonate. Theorganic phase was washed with brine, dried (Na₂SO₄), and concentrated.The resulting residue was purified by reverse-phase HPLC using a 10-90%CH₃CN/H₂O gradient (30 min) at a flow rate of 70 mL/min. The appropriatefractions were combined and freeze dried to give pureN-[2R-hydroxy-3-[[(2-amino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]carbamicacid phenylmethyl ester (0.12 g, 61%) as a white powder: FAB-MS m/z=566(M+H); HRMS: calcd. for C₂₉H₃₆N₅O₅S 566.2437 (M+H), found 566.2434.

EXAMPLE 51

Preparation of2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazole-5-yl)sulfonyl](2-methylpropyl)-amino]-1S-(phenylmethyl)propyl]carbamicacid phenylmethyl ester (2.5 g, 0.4 mmol) in MeOH (10 mL) and THF (50mL) was hydrogenated in the presence of 10% Pd/C (1.2 g) at roomtemperature at 60 psi for 16 hours. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure.The resulting residue was triturated with ether and filtered. The solidsubstance thus obtained was washed with ether and dried in vacuo toafford pure2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine(1.5 g, 77%) as an off white powder: R_(t)=12.8 min; FAB-MS m/z=490(M+H); HRMS: calcd. for C₂₃H₃₂N₅O₅S 490.2124 (M+H), found 490.2142.

EXAMPLE 52

Preparation ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide

Part A: Preparation ofN-[2R-hydroxy-3-[N¹-[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl]-N¹-(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-[(phenylmethoxy-carbonyl)amino]-3,3-dimethylbutanamide

To a solution of N-carbobenzyloxycarbonyl-L-tert-leucine (0.65 g, 2.45mmol) in DMF (10 mL) was added HOBt (0.5 g, 3.22 mmol) and EDC (0.49 g,2.55 mmol), and the resulting mixture was stirred at 0° C. for 2 hours.Then a solution of2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine (1.2 g, 2.45 mmol) in DMF (4 mL) and N-methyl morpholine(0.74 g, 7.3 mmol) was added, and the mixture was stirred at roomtemperature for 16 hours. The DMF was then distilled away in vacuo, andthe remaining residue was partitioned between cold 1N aqueous HCl (100mL) and EtOAc (200 mL). The organic phase was washed successively withcold 1N HCl (2×50 mL), brine (2×50 mL), 0.25 N NaOH (3×50 mL), brine,dried (Na₂SO₄) and concentrated in vacuo. The resulting residue waspurified by silica gel flash column chromatography using EtOAc as theeluent to afford 1.5 g (83%) of pureN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-[(phenylmethoxy-carbonyl)amino]-3,3-dimethyl butanamide:R_(t)=21.2 min; FAB-MS m/z=737 (M+H), HRMS: calcd. for C₃₇H₄₉N₆O₈S737.3333 (M+H), found 737.3334.

Part B: Preparation ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide

A solution ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3,3-dimethylbutanamide(4.0 g, 5.4 mmol) in MeOH (15 mL) and THF (65 mL) was hydrogenated inthe presence of 10% Pd/C (2.0 g) at room temperature at 50 psi for 16hours. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The resulting residue wastriturated with ether and filtered. The solid residue was washed withether and dried in vacuo to affordN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide(2.9 g, 88%) as a pale yellow powder. A portion of the material waspurified by reverse-phase HPLC using a 10-90% CH₃CN/H₂O gradient (30min) at a flow rate of 70 mL/min. The appropriate fractions werecombined and freeze dried to give pureN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-amino-3,3-dimethylbutanamideas a white powder: R_(t)=13.9 min; FAB-MS m/z=609 (M+Li), 603 (M+H);HRMS: calcd. for C₂₉H₄₃N₆O₆S 603.2965 (M+H), found 603.2972.

EXAMPLE 53

Preparation ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

A mixture of chloroacetic acid (0.32 g, 3.39 mmol), HOBt (0.78 g, 5.0mmol), and EDC (0.65 g, 3.39 mmol) in DMF (5 mL) was stirred at 0° C.for 1 hour, and was then added to a solution ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutanamide(2.0 g, 3.3 mmol) in DMF (5 mL). The resulting mixture was stirred at 0°C. for 2 hours, and at room temperature for 1 hour when the reaction wascomplete. The DMF was removed in vacuo. The resulting residue wasdissolved in EtOAc (50 mL) and washed successively with saturatedaqueous sodium bicarbonate (3×25 mL), brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting material wascrystallized from EtOAc to give 1.2 g (53%) of pureN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamideas a white powder: m.p. 253° C. (decomp); R_(t) 18.1 min; FAB-MS m/z=679(M+H), HRMS: calcd. for C₃₁H₄₄N₆O₇SCl 679.2681 (M+H), found 679.2690.

EXAMPLE 54

Preparation ofN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-[(N-methylaminoacetyl)amino]-3,3-dimethylbutanamide

N-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide(0.7 g, 1.03 mmol) was dissoved in THF (3.00 mL). Methylamine (0.8 mL,40% solution in water) was added and the reaction was stirred at roomtemperature for 2 hours. The mixture was diluted with water (10 mL), andextracted with ethyl acetate (2×20 mL). The combined organic extractswere washed with brine, dried (Na₂SO₄), and concentrated in vacuo. Theresulting residue was purified by reverse-phase HPLC using a 5-70%CH₃CN/H₂O gradient (30 min) at a flow rate of 70 mL/min. The appropriatefractions were combined and freeze dried to give pureN-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S-[(N-methylaminoacetyl)amino]-3,3-dimethylbutanamideas a white powder: R_(t) 14.1 min; FAB-MS m/z=674 (M+H); HRMS:C₃₂H₄₈N₇O₇S calcd. 674.3336 (M+H), found 674.3361.

EXAMPLE 55

Preparation of N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

Part A: Preparation of[2R-hydroxy-3-[(4-aminophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid t-butyl ester

A mixture of[2R-hydroxy-3-[(4-aminophenylsulfonyl)(2-methylpropyl)-amino]-1S-(phenylmethyl)propylamine3.7 g (9.45 mmol) and BOC-ON (2.33 g, 9.45 mmol) and triethylamine(0.954 g, 9.45 mmol) in tetrahydrofuran (60 mL) was stirred for 16 h andconcentrated in vacuo. The residue was dissolved in dichloromethane (200mL), washed with sodium hydroxide (1N, 100 mL), citric acid (5%, 100mL), dried (MgSO₄), and concentrated to afford 1.18 g (94%) of thedesired product as a white solid.Part B: Preparation of[2R-Hydroxy-3-[(2-aminobenzothiazole-6-sulfonyl)-(2-methylpropyl)amino]-1S-(phenylmethyl)propylcarbamicacid t-butyl ester

The[2R-hydroxy-3-[(4-aminophenylsulfonyl)(2-methylpropyl)]amino]-1S-(phenylmethyl)propylcarbamicacid t-butyl ester 1.12 g (2.279 mmol) was added to a well mixed powderof anhydrous copper sulfate (4.48 g) and potassium thiocyanate (5.60 g)followed by dry methanol (35 mL) and the rsulting black-brown suspensionwas heated at reflux for 2 h. The reaction mixture turned grey. Thereaction mixture was filtered and the filtrate was diluted with water(50 mL) and heated at reflux. Ethanol was added to the reaction mixture,cooled and filtered. The filtrate upon concentration afforded a rseiduewhich was chromatographed (ethyl acetate:methanol 90:10) to afford 0.80g (78%) of the deprotected compound as a solid. This was directlyreprotected via the following procedure; (2.25 g, 5.005 mmol) BOC-ON(1.24 g), and triethylamine (0.505 g, 5.005 mmol) in tetrahydrofuran (20mL) was stirred at room temperature for 18 h. The reaction mixture wasconcentrated and the residue was dissolved in dichloromethane (200 mL)and was washed with sodium hydroxide (1N, 100 mL), citric acid (5%, 100mL) dried (Mg SO₄) and concentrated to afford a residue which waschromatographed (ethyl acetate:hexane 3:1) to afford 1.8 g (65%) of thedesired product as a solid.Part C: Preparation of [2R-hydroxy-3-[(benzothiazole-6-sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl) propylcarbamic acid t-butylester

The product of part B above (1.80 g, 3.2755 mmol) was added to asolution of isoamylnitrite (0.88 mL) in dioxane (20 mL) and the mixturewas heated at 85° C. After the cessation of evolution of nitrogen, thereaction mixture was concentrated and the residue was purified bychromatography (hexane:ethyl acetate 1:1) to afford 1.25 g (78%) of thedesired product as a solid.Part D: Preparation of[2R-hydroxy-3-[(benzothiazole-6-sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propylamine.hydrochloride

The product of part C above was deprotected via the following procedure;(1.25 g, 2.3385 mmol) was added dioxane/HCl (4N, 10 mL) and was stirredat room temperature for 2 h and concentrated. Excess HCl was chased withtoluene to afford 1.0 g (quantitative yield) of the desired product asits HCl salt.Part E: Preparation ofN-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)-amino]-1S-(phenylmethyl)propyl)-2S-[[(N-benzyloxy)carbonyl]amino]-3,3-dimethyl butanamide

A mixture of N-benzyloxycarbonyl-t-butylglycine (2.0 g, 7.538 mmol),HOBT (1.02 g, 7.55 mmol), and EDC (1.45 g, 7.55 mmol) in DMF (20 mL) wasstirred at room temperature for 1 hour. Then[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine hydrochloride (3.825 g, 7.54 mmol) and N-methylmorpholine(3.80 g) were added and the stirring continued for 18 hours. The DMF wasremoved in vacuo, the residue was dissolved in dichloromethane (500 mL),and washed with citric acid (1N, 100 mL), sodium bicarbonate (100 mL),brine (200 mL), dried, filtered, and concentrated to afford 4.69 g (91%)of pure N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[N-(phenylmethoxycarbonyl)amino]-3,3-dimethylbutanamide.Part F: Preparation ofN-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-(amino)-3,3-dimethylbutanamide.dihydrobromide

A solution ofN-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[N-(phenylmethoxycarbonyl)amino]-3,3-dimethyl butanamide(4.69 g, 6.89 mmol) in dichloroethane (200 mL) was treated with HBr (48%in acetic acid, 7.1 mL), and the reaction mixture was stirred for 2hours at room temperature. The reaction mixture was concentrated and theresidue was washed with diethyl ether several times to afford 4.88 g ofthe desired dihydrobromide product as a powder: high resolution FAB-MSCalcd for C₂₇H₃₈N₄O₄S₂: 547.2413, found: 547.2429 (M+H).

Part G: Preparation ofN-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

A mixture ofN-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-(amino)-3,3-dimethylbutanamide dihydrobromide (3.5 g, 4.9388mmol), chloroacetic anhydride (0.929 g, 5.44 mmol) and triethylamine(1.097 g, 10.86 mmol) in dichloromethane (35 mL) was stirred at roomtemperature for 16 hours. The reaction mixture was washed with citricacid (1N, 30 mL), sodium bicarbonate (30 mL), brine (30 mL), dried,filtered and concentrated to afford 3.0 g of the desired product.

EXAMPLE 56

Preparation of2S-[[N-(phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

To a solution of 2.0 g (3.3 mmol)2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidein 10 mL of tetrahydrofuran was added 2.2 mL of benzylamine. After 1hour, an additional 2.0 mL of benzylamine was added. After 30 min, thereaction mixture was concentrated in vacuo, hexane was added and theheaxne decanted away from the oil. The oil was dissolved in ethylacetate, washed with saturated sodium bicarbonate, brine, dried withmagnesium sulfate, filtered and concentrated the crude product. This wasdissolved in diethyl ether and hexane added, which resulted in aninsoluble oil. The solvents were decanted from the oil and the oilyresidue concentrated under reduced pressure to afford 1.85 g. This wasdissolved in ethyl acetate and poured into hexane which resulted in aninsoluble oil. The solvents were decanted and the residue concentratedto afford 1.56 g of the desired product, m/e=687 (M+Li).

EXAMPLE 57

Preparation of2S-[[N,N-(dimethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

To a solution of 2.0 g (3.3 mmol)2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidein 8 mL of tetrahydrofuran was added 8.2 mL of 40% aqueousdimethylamine. After 2 hours, the solvents were removed in vacuo. Theresidue was dissolved in ethyl acetate, washed with brine, dried withmagnesium sulfate, filtered and concentrated in vacuo to afford 1.97 gof the desired product, m/e=619 (M+H).

EXAMPLE 58

Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

Part A: A solution of 1.0 grams (4.9 mmol) of N-t-BOC-N-methyl-D-alaninein 5 mL of anhydrous DMF was cooled to 0° C., charged with 0.9 grams(6.4 mmol) of HOBT and 0.9 grams (4.9 mmol) of EDC and stirred for fourhours. The reaction solution was then charged with a solution of 2.3grams (4.3 mol) of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamideand 1.3 grams (12.8 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 15 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated to afford 2.9 grams of the desired product asa white solid, m/e=725 (M+Li).

Part B: A solution of 2.5 g of the compound from part A in 20 nm 4NHCl-dioxane and stirred for 1 hour at room temperature. Concentration invacuo followed by trituration with Et₂O yielded 2.2 g white solid. Theproduct was vacumn dried over P₂O₅ to yield 2.1 g final product.

EXAMPLE 59

Preparation of2S-[[2R-aminopropionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A: Preparation of 2S-[[2R-[(phenylmethoxycarbonyl)amino]propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

To a solution of 10 g (4.5 mmol) of N-carbobenzyloxycarbonyl-D-alanineand 1.03 g of HOBt in 9 mL of anhydrous N,N-dimtheylformamide at 0° C.,was added 0.95 g of EDC coupling agent. After 2 hours at 0° C., 2.39 g(4.5 mmol) of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidewas added. After stirring overnite, the solvents were removed in vacuo,the residue was dissolved in ethyl acetate, washed with 5% potassiumhydrogen sulfate, saturated sodium bicarbonate, brine, dried withmagnesium sulfate, filtered and concentrated in vacuo to afford 3.2 g ofcrude material. This was chromatographed on 150 g of silica gel using50-80% ethyl acetate/hexane as eluent to afford 2.3 g of the desiredproduct, which was used directly in the next step.

Part B: Preparation of2S-[[2R-aminopropionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 2.3 g of the product of Part A in 20 mL of methanol washydrogenated over 1.0 g of 4% Palldium-on-carbon under 50 psig ofhydrogen for 1 hour. The catalyst was removed by filtration. Thesolvents were removed in vacuo to afford 1.5 g of the desired product,m/e=611 (M+Li).

EXAMPLE 60

Preparation ofN-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamidePart A: Preparation ofN-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3S-methylpentanamide

A solution of 5.8 grams (22.0 mmol) of N-CBZ-L-isoleucine in 45 mL ofanhydrous N,N-dimethylformamide (DMF) was cooled to 0° C. and chargedwith 3.9 grams (28.7 mmol) of N-hydroxybenzotriazole (HOBT) and 4.2grams (22.0 mmol) of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC). The ice bath was removed after 20 minutes andstirring was continued for an additional 40 minutes. The reactionsolution was then charged with a solution of 8.0 grams (19.1 mmol) of2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamineand 2.2 grams (22.0 mmol) of 4-methylmorpholine in 25 mL of anhydrousDMF and stirred for 15 hours. The solvents were removed in vacuo and theresidue was partitioned between 300 mL of ethyl acetate and 120 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 120 mL each of saturated sodiumbicarbonate solution, water, and brine, then dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 16.7 grams ofcrude material. The crude material was crystallized from ethanol, thesolid was isolated by filtration, rinsed with one 50 mL portion ofhexane, and air-dried to yield 12.0 grams (94%) of the desired product,m/e=672 (M+Li).

Part B: Preparation ofN-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide

A Fischer-Porter bottle equipped with a magnetic stir bar was chargedwith 11.9 grams (17.9 mmol) of the product from Part A and 75 mL oftetrahydrofuran (THF). The solution was hydrogenated in the presence of5 grams of 10% palladium-on-carbon catalyst (50% water by weight) under50 psig of hydrogen for 4 hours at room temperature. The catalyst wasremoved by filtration, and the solvents removed in vacuo. The residuewas dissolved in 300 mL of ethyl acetate, washed with 120 mL each ofsaturated sodium bicarbonate solution and of brine, then dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to afford 8.8 grams of the desired product, m/e=532 (M+H).

EXAMPLE 61

Preparation ofN-[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide

Part A: Preparation of N-[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethoxycarbonyl)amino]-3S-methylpentanamide

A solution of 6.0 grams (22.6 mmol) of N-CBZ-L-isoleucine in 45 mL ofanhydrous DMF was cooled to 0° C. and charged with 4.0 grams (29.5 mmol)of HOBT and 4.3 grams (22.6 mmol) of EDC. The ice bath was removed after20 minutes and stirring was continued for an additional 40 minutes. Thereaction solution was then charged with a solution of 7.4 grams (19.7mmol) of2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propylamineand 2.3 grams (22.6 mmol) of 4-methylmorpholine in 25 mL of anhydrousDMF and stirred for 18 hours. The solvents were removed in vacuo and theresidue was partitioned between 300 mL of ethyl acetate and 120 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 120 mL each of saturated sodiumbicarbonate solution, water and brine, then dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 13 grams of crudematerial. The crude material crystallized from ethanol, the solid wasisolated by filtration, rinsed with one 50 mL portion of hexane, andair-dried to yield 10.3 grams (84%) of the desired product, m/e=630(M+Li).

Part B: Preparation of N-[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide

A Fischer-Porter bottle equipped with a magnetic stir bar was chargedwith 10.2 grams (16.4 mmol) of the product from Part A and 75 mL oftetrahydrofuran (THF). The solution was hydrogenated in the presence of4 grams of 10% palladium-on-carbon catalyst (50% water by weight) under50 psig of hydrogen for 3 hours at room temperature. The catalyst wasremoved by filtration, and the solvents removed in vacuo. The residuewas dissolved in 300 mL of ethyl acetate and washed with 120 mL each ofsaturated sodium bicarbonate solution and brine, then dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo toafford 7.4 grams of the desired product, m/e=490 (M+H).

EXAMPLE 62

Preparation of2S-[[2S-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

Part A: Preparation of2S-[[2S-[N-(tert-butoxycarbonyl)-N-(methyl)amino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 1.0 grams (4.9 mmol) of N-t-BOC-N-methyl-L-alanine in 5 mLof anhydrous DMF was cooled to 0° C., charged with 0.9 grams (6.4 mmol)of HOBT and 0.9 grams (4.9 mmol) of EDC and stirred for four hours. Thereaction solution was then charged with a solution of 2.3 grams (4.3mmol) of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamideand 1.3 grams (12.8 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 15 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to afford 3.1 grams (100%) of thedesired product as a white solid, m/e=725 (M+Li).

Part B: Preparation of2S-[[2S-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 3.1 grams (4.3 mmol) of the product from Part A in 10 mLof 1,4-dioxane was charged with 20 mL (40 mmol) of 4N HCl in dioxanesolution and stirred for 2 hours. The solvents were removed in vacuo toyield a white solid. The solid was triturated with diethyl ether andisolated by filtration. This solid was triturated with 35%acetonitrile/65% water (both with 1% HCl) and again isolated byfiltration. The solid was dried by sequentially adding then removingunder reduced pressure three volume of ethanol then three volumes ofwater. Final drying was done over phosphorous pentaoxide (P₂O₅) underreduced pressure at room temperature and yielded 1.3 grams (46%) of thedesired product as the HCl salt, m/e=625 (M+Li)

EXAMPLE 63

Preparation of2S-[[2S-aminopropionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A: Preparation of 2S-[[2S-[(phenylmethoxycarbonyl)amino]propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 1.1 grams (4.9 mmol) of N-CBZ-L-alanine in 5 mL ofanhydrous DMF was cooled to 0° C., charged with 0.9 grams (6.4 mmol) ofHOBT and 1.0 grams (4.9 mmol) of EDC and stirred for two hours. Thereaction was then charged with a solution of 2.3 grams (4.3 mmol) of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamideand 1.3 grams (12.9 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 18 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated to afford 3.2 grams of crude material. Thecrude material was crystallized from ethanol, the solid was isolated byfiltration, rinsed with one 40 mL portion of hexane, and air-dried toyield 3.0 grams (84%) of the desired product, m/e=745 (M+Li).

Part B: Preparation of2S-[[2S-aminopropionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A Fischer-Porter bottle equipped with a magnetic stir bar was chargedwith 2.9 grams (3.9 mmol) of the product from Part A and 20 mL oftetrahydrofuran (THF). The solution was hydrogenated in the presence of1.3 grams of 10% palladium-on-carbon catalyst (50% water by weight)under 50 psig of hydrogen for 2 hours at room temperature. The catalystwas removed by filtration, and the solvents removed under reducedpressure. The residue was dissolved in 150 mL of ethyl acetate andwashed with 50 mL each of saturated sodium bicarbonate solution andbrine, then dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to afford 2.1 grams of crudematerial. Purification was accomplished by flash chromatography onsilica gel using 2-6% methanol/methylene chloride and yielded 1.9 grams(83%) of the desired product as a white solid, m/e=605 (M+H).

EXAMPLE 64

Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloridesalt

Part A: Preparation of2S-[[2R-[N-(tert-butoxycarbonyl)-N-(methyl)amino]propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide

A solution of 0.7 grams (3.3 mmol) of N-t-BOC-N-methyl-D-alanine in 5 mLof anhydrous DMF was cooled to 0° C., charged with 0.7 grams (5.0 mmol)of HOBT and 0.7 grams (3.8 mmol) of EDC and stirred for three hours. Thereaction solution was then charged with a solution of 1.8 grams (3.3mmol) of2S-amino-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamideand 1.0 grams (9.9 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 16 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water, and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to yield the crude material.Purification was accomplished using flash chromatography on silica gelusing 30-50% ethyl acetate/methylene chloride and yielded 1.9 grams(79%) of the desired product as a white solid, m/e=725 (M+Li).

Part B: Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloridesalt

A solution of 1.9 grams (4.3 mmol) of the product from Part A in 10 mLof 1,4-dioxane was charged with 20 mL (40 mmol) of 4N HCl in dioxanesolution and stirred for 2 hours. The solvents were removed in vacuo toyield a white solid. The solid was dried by sequentially adding thenremoving in vacuo three volumes of ethanol then three volumes of water.Final drying was done over phosphorous pentaoxide (P₂O₅) under reducedpressure at room temperature and yielded 1.5 grams (88%) of the desiredproduct as the HCl salt, m/e=625 (M+Li).

EXAMPLE 65

Preparation of2S-[[N-(phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide

A solution of 1.5 grams (2.5 mmol) of2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide in 10 mL of tetrahydrofuran (THF) and 0.5 mL of water wascharged with 5.3 grams (49.2 mmol) of benzylamine and stirred for 17hours. The solvents were removed in vacuo and the residue waspartitioned between 150 mL of ethyl acetate and 50 mL of saturatedsodium bicarbonate solution, the layers were separated and the organiclayer was washed with 50 mL of brine, then dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to afford 2.5grams of crude material. Purification was accomplished using flashchromatography on silica gel using 0-6% methanol/methylene chloride andyielded 1.6 grams (96%) of the desired product as a white solid, m/e=687(M+Li).

EXAMPLE 66

Preparation of N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(N-cyclopropylamino)acetyl]amino]-3S-methylpentanamide

A solution of 1.5 grams (2.5 mmol) of2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamidein 10 mL of THF and 0.5 mL of water was charged with 2.8 grams (49.2mmol) of cyclopropylamine and stirred for 16 hours. The solvents wereremoved in vacuo and the residue was partitioned between 150 mL of ethylacetate and 50 mL of saturated sodium bicarbonate solution, the layerswere separated and the organic layer was washed with 50 mL of brine,then dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo to afford 1.5 grams of the desired product as a white solid,m/e=637 (M+Li), 98% by HPLC.

EXAMPLE 67

Preparation of2S-[[N-(2-methoxyethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide

A solution of 1.5 grams (2.5 mmol) of2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(1,3-benzodiox-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide in 10 mL of THF and 0.5 mL of water was charged with 3.7grams (49.2 mmol) of 2-methoxyethylamine and stirred for 18 hours. Thesolvents were removed in vacuo and the residue was partitioned between150 mL of ethyl acetate and 50 mL of saturated sodium bicarbonatesolution, the layers were separated and the organic layer was washedwith 50 mL of brine, then dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to afford 2 grams of crude material.Purification was accomplished using flash chromatography on silica gelusing 0-6% methanol/methylene chloride and yielded 1.3 grams (81%) ofthe desired product as a white solid, m/e=655 (M+Li).

EXAMPLE 68

Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

Part A: Preparation of2S-[[2R-[N-(tert-butoxycarbonyl)-N-(methyl)amino]propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 0.7 grams (3.3 mmol) of N-t-BOC-N-methyl-D-alanine in 5 mLof anhydrous DMF was cooled to 0° C., charged with 0.7 grams (5.0 mmol)of HOBT and 0.7 grams (3.8 mmol) of EDC and stirred for three hours. Thereaction solution was then charged with a solution of 1.7 grams (3.3mmol) of2S-amino-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamideand 1.0 grams (9.9 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 18 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water, and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to yield 2.3 grams (100%) of thedesired product as a white solid, m/e=711 (M+Li).

Part B: Preparation of 2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide.hydrochloride

A solution of 2.3 grams (3.2 mmol) of the product from Part A in 10 mLof 1,4-dioxane was charged with 20 mL (40 mmol) of 4N HCl in dioxanesolution and stirred for 2 hours. The solvents were removed in vacuo toyield a white solid. The solid was dried by sequentially adding thenremoving in vacuo three volumes of ethanol then three volumes of water.Final drying was done over phosphorous pentaoxide (P₂O₅) under reducedpressure at room temperature and yielded 1.9 grams (90%) of the desiredproduct as the HCl salt, m/e=611 (M+Li).

EXAMPLE 69

Preparation of2S-[[phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A: Preparation of N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[(chloroacetyl)amino]-3,3-dimethylbutanamide

A solution of 4.4 grams (8.4 mmol) of2S-amino-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide and 1.3 grams(10.1 mmol) of diisopropylethylamine in 30 mL of anhydrous methylenechloride was cooled in an ice bath and charged with 1.2 grams (7.1 mmol)of chloroacetic anhydride and stirred for one-half hour. HPLC analysisat this time showed the reaction to be 83% complete. The solution wascharged with an additional 0.2 gram (1.2 mmol) of chloroacetic anhydrideand stirred for 15 hours. The solvents were removed in vacuo and theresidue was partitioned between 300 mL of ethyl acetate and 100 mL of 5%citric acid solution, the layers were separated and the organic layerwas washed with 100 mL each of saturated sodium bicarbonate solution,water and brine, then dried over anhydrous magnesium sulfate, filteredand concentrated to afford 5.1 grams of crude material. Purification wasaccomplished using flash chromatography on silica gel using 30-50% ethylacetate/hexane and yielded 4.1 grams (82%) of the desired product as awhite solid, m/e=602 (M+Li).

Part B: Preparation of2S-[[N-(phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 1.3 grams (2.2 mmol) of the product from

Part A in 12 mL of THF and 0.5 mL of water was charged with 4.8 grams(44.6 mmol) of benzylamine and stirred for 16 hours. The solvents wereremoved in vacuo and the residue was partitioned between 150 mL of ethylacetate and 50 mL of saturated sodium bicarbonate solution, the layerswere separated and the organic layer was washed with 50 mL of brine,then dried over anhydrous magnesium sulfate, filtered and concentratedto yield the crude material as an oil. Purification was accomplishedusing flash chromatography on silica gel using 0-4% methanol/methylenechloride and yielded 1.3 grams (87%) of the desired product as a whitesolid, m/e=673 (M+Li).

EXAMPLE 70

Preparation of2S-[[(N-cyclopropylamino)acetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 1.3 grams (2.2 mmol) of2S-[[chloroacetyl]amino-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidein 12 mL of THF and 0.5 mL of water was charged with 2.6 grams (44.6mmol) of cyclopropylamine and stirred for 18 hours. The solvents wereremoved in vacuo and the residue was partitioned between 150 mL of ethylacetate and 50 mL of saturated sodium bicarbonate solution, the layerswere separated and the organic layer was washed with 50 mL of brine,then dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo to yield 1.3 grams (93%) of the desired product as a whitesolid, m/e=623 (M+Li).

EXAMPLE 71

Preparation of2S-[[N-(2-methoxyethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

A solution of 1.3 grams (2.2 mmol) of2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidein 12 mL of THF and 0.5 mL of water was charged with 3.4 grams (44.6mmol) of 2-methoxy ethylamine and stirred for 17 hours. The solventswere removed in vacuo and the residue was partitioned between 150 mL ofethyl acetate and 50 mL of saturated sodium bicarbonate solution, thelayers were separated and the organic layer was washed with 50 mL ofbrine, then dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to yield the crude material. Purification wasaccomplished using flash chromatography on silica gel using 0-6%methanol/methylene chloride and yielded 1.1 grams (77%) of the desiredproduct as a white solid, m/e=641 (M+Li).

EXAMPLE 72

Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxpyhenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloridesalt

Part A: Preparation of 2S-[[2R—(N-(tert-butoxycarbonyl)-N-(methyl)amino]propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide

A solution of 0.7 grams (3.3 mmol) of N-t-BOC-N-methyl-D-alanine in 5 mLof anhydrous DMF was cooled to 0° C., charged with 0.7 grams (5.0 mmol)of HOBT and 0.7 grams (3.8 mmol) of EDC and stirred for three hours. Thereaction solution was then charged with a solution of 1.7 grams (3.3mmol) of2S-amino-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamideand 1.0 grams (9.9 mmol) of 4-methylmorpholine in 5 mL of anhydrous DMFand stirred for 16 hours. The solvents were removed in vacuo and theresidue was partitioned between 150 mL of ethyl acetate and 50 mL of 5%potassium hydrogen sulfate solution. The layers were separated, and theorganic layer was washed with 50 mL each of saturated sodium bicarbonatesolution, water, and brine, then dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to yield the crude material.Purification was accomplished using flash chromatography on silica gelusing 30-50% ethyl acetate/hexane and yielded 1.6 grams (70%) of thedesired product as a white solid, m/e=711 (M+Li).

Part B: Preparation of Preparation of2S-[[2R-(N-methylamino)propionyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-amino-3S-methylpentanamide.hydrochloride salt

A solution of 1.6 grams (2.2 mmol) of the product from Part A in 10 mLof 1,4-dioxane was charged with 20 mL (40 mmol) of 4N HCl in dioxanesolution and stirred for 2 hours. The solvents were removed in vacuo toyield a white solid. The solid was dried by sequentially adding thenremoving under reduced pressure three volumes of ethanol then threevolumes of water. Final drying was done over phosphorous pentaoxide(P₂O₅) under reduced pressure at room temperature and yielded 1.2 grams(86%) of the desired product as the HCl salt, m/e=611 (M+Li).

EXAMPLE 73

Preparation of2S-[[N-(phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide

Part A: Preparation of2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide

A solution of 5.5 grams (10.6 mmol) of2S-amino-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamideand 1.6 grams (12.7 mmol) of diisopropylethylamine in 30 mL of anhydrousmethylene chloride was cooled in an ice bath and charged with 1.5 grams(9.0 mmol) of chloroacetic anhydride and stirred for one-half hour. HPLCanalysis at this time showed the reaction to be 82% complete. Thesolution was charged with an additional 0.3 gram (1.8 mmol) ofchloroacetic anhydride and stirred for 16 hours. The solvents wereremoved in vacuo and the residue was partitioned between 300 mL of ethylacetate and 100 mL of 5% citric acid solution, the layers were separatedand the organic layer was washed with 100 mL each of saturated sodiumbicarbonate solution, water and brine, then dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to afford 6.2grams of the desired product as a white solid, m/e=602 (M+Li).

Part B: Preparation of2S-[[N-(phenylmethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3S-methylpentanamide

A solution of 2.0 grams (3.4 mmol) of the chloroacetyl product from PartA in 12 mL of THF and 0.5 mL of water was charged with 7.2 grams (67.1mmol) of benzylamine and stirred for 64 hours. The solvents were removedin vacuo and the residue was partitioned between 150 mL of ethyl acetateand 50 mL of saturated sodium bicarbonate solution, the layers wereseparated and the organic layer was washed with 50 mL each of water andbrine, then dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to yield the crude material as an oil.Purification was accomplished using flash chromatography on silica gelusing 0-4% methanol/methylene chloride and yielded 1.8 grams (80%) ofthe desired product as a white solid, m/e=673 (M+Li).

EXAMPLE 74

Preparation of N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S-[[(N-cyclopropylamino)acetyl]amino]-3S-methylpentanamide

A solution of 2.0 grams (3.4 mmol) of2-S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamidein 12 mL of THF and 0.5 mL of water. The solution was charged with 3.8grams (67.1 mmol) of cyclopropylamine and stirred for 64 hours Thesolvents were removed in vacuo and the residue was partitioned between150 mL of ethyl acetate and 50 mL of saturated sodium bicarbonatesolution, the layers were separated and the organic layer was washedwith 50 mL each of water and brine, then dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to yield the crude materialas a white solid. Purification was accomplished using flashchromatography on silica gel using 1-4% methanol/methylene chloride andyielded 18 grams (81%) of the desired product as a white solid, m/e=623(M+Li).

EXAMPLE 75

Preparation of2S-[[N-(2-methoxyethyl)aminoacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide

A solution of 2.0 grams (3.4 mmol) of2S-[[chloroacetyl]amino]-N-[2R-hydroxy-3-[[(4-methoxybenzene)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethylpropyl]-3S-methylpentanamide in 12 mL of THF and 0.5 mL of water wascharged with 5.0 grams (67.1 mmol) of 2-methoxyethylamine and stirredfor 64 hours. The solvents were removed in vacuo and the residue waspartitioned between 150 mL of ethyl acetate and 50 mL of saturatedsodium bicarbonate solution, the layers were separated and the organiclayer was washed with 50 mL each of water and brine, then dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to yieldthe crude material. Purification was accomplished using flashchromatography on silica gel using 0-6% methanol/methylene chloride andyielded 1.6 grams (76%) of the desired product as a white solid, m/e=641(M+Li).

EXAMPLE 76

Following the procedures of the previous Examples, the compounds setforth in Tables 2 through 15 can be prepared.

TABLE 2

Entry R³ R⁴ 1 isobutyl 2-methyl-1,3-benzodioxol-5-yl 2 isobutyl2-methyl-1,3-benzodioxol-5-yl 3 cyclopentylmethyl2-methyl-1,3-benzodioxol-5-yl 4 cyclohexylmethyl2-methyl-1,3-benzodioxol-5-yl 5 cyclopentylmethyl 1,3-benzodioxol-5-yl 6cyclohexylmethyl 1,3-benzodioxol-5-yl 7 cyclopentylmethylbenzofuran-5-yl 8 cyclohexylmethyl benzofuran-5-yl 9 cyclopentylmethyl2,3-dihydrobenzofuran-5-yl 10 cyclohexylmethyl2,3-dihydrobenzofuran-5-yl 11 isobutyl 1,3-benzodioxol-5-yl 12 isobutylbenzofuran-5-yl 13 isobutyl 2,3-dihydrobenzofuran-5-yl 14 isobutyl1,4-benzodioxan-6-yl 15 isoamyl 1,3-benzodioxol-5-yl 16 isoamyl2,3-dihydrobenzofuran-5-yl 17 isoamyl 1,4-benzodioxan-6-yl 18 isobutylbenzothiazol-6-yl 19 isobutyl 2-amino-benzothiazol-6-yl 20 isobutylbenzoxazol-5-yl 21 cyclopentylmethyl 2,2-difluoro-1,3-benzodioxol-5-yl22 cyclohexylmethyl 2,2-difluoro-1,3-benzodioxol-5-yl

TABLE 3A

Entry A

TABLE 3B

Entry A

TABLE 3C

Entry A

TABLE 3D

Entry A

TABLE 3E

Entry A

TABLE 3F

Entry A

TABLE 3G

Entry A

TABLE 3H

Entry A

TABLE 4A

Entry A

TABLE 4B

Entry A

TABLE 4C

Entry A

TABLE 4D

Entry A

TABLE 4E

Entry A

TABLE 4F

Entry A

TABLE 4G

Entry A

TABLE 4H

Entry A

TABLE 5A

Entry A

TABLE 5B

Entry A

TABLE 5C

Entry A

TABLE 5D

Entry A

TABLE 5E

Entry A

TABLE 5F

Entry A

TABLE 5G

Entry A

TABLE 5H

Entry A

TABLE 6A

Entry A

TABLE 6B

Entry A

TABLE 6C

Entry A

TABLE 6D

Entry A

TABLE 6E

Entry A

TABLE 6F

Entry A

TABLE 6G

Entry A

TABLE 6H

Entry A

TABLE 7A

Entry A

TABLE 7B

Entry A

TABLE 7C

Entry A

TABLE 7D

Entry A

TABLE 7E

Entry A

TABLE 7F

Entry A

TABLE 7G

Entry A

TABLE 7H

Entry A

TABLE 8A

Entry R² (CH₃)₂CHCH₂— (4-FC₆H₅)CH₂— CH₃CH₂CH₂CH₂— (naphth-2-yl)CH₂—CH₃SCH₂CH₂— C₆H₁₁CH₂— C₆H₅CH₂— C₆H₅SCH₂— (4-CH₃OC₆H₅)CH₂—(naphth-2-yl)SCH₂—

TABLE 8B

Entry R² (CH₃)₂CHCH₂— (4-FC₆H₅)CH₂— CH₃CH₂CH₂CH₂— (naphth-2-yl)CH₂—CH₃SCH₂CH₂— C₆H₁₁CH₂— C₆H₅CH₂— C₆H₅SCH₂— (4-CH₃OC₆H₅)CH₂—(naphth-2-yl)SCH₂—

TABLE 8C

Entry R² (CH₃)₂CHCH₂— (4-FC₆H₅)CH₂— CH₃CH₂CH₂CH₂— (naphth-2-yl)CH₂—CH₃SCH₂CH₂— C₆H₁₁CH₂— C₆H₅CH₂— C₆H₅SCH₂— (4-CH₃OC₆H₅)CH₂—(naphth-2-yl)SCH₂—

TABLE 8D

Entry R² (CH₃)₂CHCH₂— (4-FC₆H₅)CH₂— CH₃CH₂CH₂CH₂— (naphth-2-yl)CH₂—CH₃SCH₂CH₂— C₆H₁₁CH₂— C₆H₅CH₂— C₆H₅SCH₂— (4-CH₃OC₆H₅)CH₂—(naphth-2-yl)SCH₂—

TABLE 9A

Entry R³ —CH₂CH₂CH₃ —CH₂CH₂CH₂CH₃

—CH₂CH(CH₃)₂ —CH₂CH₂CH(CH₃)₂

TABLE 9B

Entry R³ —CH₂CH₂CH₃ —CH₂CH₂CH₂CH₃

—CH₂CH(CH₃)₂ —CH₂CH₂CH(CH₃)₂

TABLE 9C

Entry R³ —CH₂CH₂CH₃

—CH₂CH₂CH₂CH₃

—CH₂CH(CH₃)₂

—CH₂CH₂CH(CH₃)₂

TABLE 9D

Entry R³ —CH₂CH₂CH₃

—CH₂CH₂CH₂CH₃

—CH₂CH(CH₃)₂

—CH₂CH₂CH(CH₃)₂

TABLE 10A

Entry R¹

TABLE 10B

Entry R¹

TABLE 10C

Entry R¹

TABLE 10D

Entry R¹

TABLE 10E

Entry R¹

TABLE 10F

Entry R¹

TABLE 11A

Entry R⁴

TABLE 11B

Entry R⁴

TABLE 11C

Entry R⁴

TABLE 11D

Entry R⁴

TABLE 11E

Entry R⁴

TABLE 11F

Entry R⁴

TABLE 12A

Entry R⁴

TABLE 12B

Entry R⁴

TABLE 12C

Entry R⁴

TABLE 12D

Entry R⁴

TABLE 12E

Entry R⁴

TABLE 12F

Entry R⁴

TABLE 13A

Entry R⁴

TABLE 13B

Entry R⁴

TABLE 13C

Entry R⁴

TABLE 13D

Entry R⁴

TABLE 13E

Entry R⁴

TABLE 13F

Entry R⁴

TABLE 14A

Entry R⁴

TABLE 14B

Entry R⁴

TABLE 14C

Entry R⁴

TABLE 14D

Entry R⁴

TABLE 14E

Entry R⁴

TABLE 14F

Entry R⁴

TABLE 15A

Entry R⁴

TABLE 15B

Entry R⁴

TABLE 15C

Entry R⁴

TABLE 15D

Entry R⁴

TABLE 15E

Entry R⁴

TABLE 15F

Entry R⁴

EXAMPLE 77

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTable 16. The enzyme method is described below. The substrate is2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control is MVT-101(Miller, M. et al, Science, 246, 1149 (1989)] The assay conditions areas follows:

Assay buffer: 20 mM sodium phosphate, pH 6.4

-   -   20% glycerol    -   1 mM EDTA    -   1 mM DTT    -   0.1% CHAPS        The above described substrate is dissolved in DMSO, then diluted        10 fold in assay buffer. Final substrate concentration in the        assay is 80 μM. HIV protease is diluted in the assay buffer to a        final enzyme concentration of 12.3 nanomolar, based on a        molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10× the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

EXAMPLE 78

The effectiveness of various compounds were determined in theabove-described enzyme assay and in a CEM cell assay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4⁺ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀=the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments:

Cells Drug Virus 1. + − − 2. + + − 3. + − + 4. + + +

In experiments 2 and 4 the final concentrations of test compounds were1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) was included as a positive drug control. Test compounds weredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration did not exceed 1.5% in any case. DMSO was addedto all control wells at an appropriate concentration.

Following the addition of virus, cells were incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7, post-infection, the cells ineach well were resuspended and a 100 μp sample of each cell suspensionwas removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μL cell suspension, and the cells were incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample was added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and sampleswere incubated overnight. The absorbance at 590 nm was determined foreach sample using a Molecular Devices microplate reader. Absorbancevalues for each set of wells is compared to assess viral controlinfection, uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

TABLE 16 IC₅₀ EC₅₀ Entry Compound (nM) (nM) 1

2 18 2

2 35 3

2 4

2 85 5

2 10 6

3 24 7

2  8 8

2 9

3 17 10

2 22 11

1 12

2 13

3 14

2 15

2 16

2 17

2 18

2 19

3

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment, proplylaxisof retroviral infections and/or the prevention of the spread ofretroviral infections.

The subject compounds are also effective in preventing the growth ofretroviruses in a solution. Both human and animal cell cultures, such asT-lymphocyte cultures, are utilized for a variety of well knownpurposes, such as research and diagnostic procedures includingcalibrators and controls. Prior to and during the growth and storage ofa cell culture, the subject compounds may be added to the cell culturemedium at an effective concentration to prevent the unexpected orundesired replication of a retrovirus that may inadvertently,unknowingly or knowingly be present in the cell culture. The virus maybe present originally in the cell culture, for example HIV is known tobe present in human T-lymphocytes long before it is detectable in blood,or through exposure to the virus. This use of the subject compoundsprevents the unknowing or inadvertent exposure of a potentially lethalretrovirus to a researcher or clinician.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-1-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims. From the foregoing description, one skilled in the artcan easily ascertain the essential characteristics of this invention,and without departing from the spirit and scope thereof, can makevarious changes and modifications of the invention to adapt it tovarious usages and conditions.

1. Compound represented by the formula:

or a pharmaceutically acceptable salt, or ester thereof, wherein Rrepresents alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms,alkynyl of 2-5 carbon atoms, hydroxyalkyl of 1-3 carbon atoms,alkoxyalkyl of 1-3 alkyl and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3alkyl carbon atoms, imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂S(O)₂NH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃,—C(CH₃)₂S(O)CH₃ or —C(CH₃)₂S(O)₂CH₃; R³ represents alkyl of 1-5 carbonatoms, cycloalkyl of 5-8 ring members or cycloalkylmethyl of 3-6 ringmembers; R¹⁰ represents hydrogen, alkyl, hydroxyalkyl or alkoxyalkyl,wherein alkyl and alkoxy are each 1-3 carbon atoms; R¹¹ represents alkylof 1-5 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, alkoxyalkyl of1-4 alkyl carbon atoms, benzyl, imidazolylmethyl, —CH₂CH₂CONH₂,—CH₂CONH₂, —CH₂CH₂SCH₃ or —CH₂SCH₃ or sulfone or sulfoxide derivativesthereof; R⁴ represents aryl benzo fused 5 to 6 ring member heteroaryl orbenzo fused 5 to 6 ring member heterocyclo; or a radical of the formula

 wherein A and B each independently represent O, S, SO or SO₂; R⁶represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro; R⁷represents hydrogen, deuterium, methyl, fluoro or chloro; or a radicalof the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5carbon atoms, alkynyl of 2 to 5 carbon atoms, aralkyl of 1 to 5 alkylcarbon atoms, heteroaralkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, aminoalkyl of 2 to 5 carbon atoms, N-mono-substituted orN,N-disubstituted aminoalkyl of 2 to 5 alkyl carbon atoms wherein saidsubstituents are alkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkylcarbon atoms, carboxyalkyl of 1 to 5 carbon atoms, alkoxycarbonylalkylof 1 to 5 alkyl carbon atoms, cyanoalkyl of 1 to 5 carbon atoms orhydroxyalkyl of 2 to 5 carbon atoms; R²¹ represents hydrogen or alkyl of1 to 3 carbon atoms; or the radical of formula —NR²⁰R²¹ represents a 5to 6 ring member heterocyclo; and R²² represents alkyl of 1 to 3 carbonatoms or R²⁰R²¹N-alkyl radical of 1 to 3 alkyl carbon atoms; and R¹² andR¹³ each independently represent hydrogen, alkyl, aralkyl,heteroaralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl,aryl or heteroaryl, wherein alkyl is 1-5 carbon atoms, cycloalkyl is 3-6ring membered cycloalkyl optionally benzo fused, and heteroaryl is 5 to6 ring membered heteroaryl optionally benzo fused.
 2. Compound of claim1, or a pharmaceutically acceptable salt, or ester thereof, wherein R¹represents alkyl of 1-4 carbon atoms, alkenyl of 2-3 carbon atoms,alkynyl of 3-4 carbon atoms, cyanomethyl, imidazolylmethyl, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂S(O)₂NH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃,—C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃ or —C(CH₃)₂S(O)₂CH₃; R³ represents alkylof 1-5 carbon atoms, cycloalkylmethyl of 3-6 ring members, cyclohexyl,or cycloheptyl; and, R⁴ represents phenyl, 2-naphthyl, 4-methoxyphenyl,4-hydroxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl, 4-aminophenyl,2-amino-benzothiazol-5-yl, 2-amino-benzothiazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or aradical of the formula

 wherein A and B each represent O; R⁶ represents deuterium, methyl,ethyl, propyl, isopropyl or fluoro; and R⁷ represents hydrogen,deuterium, methyl or fluoro; or a radical of the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, alkyl of 1 to 5 carbon atoms, phenylalkyl of 1 to 3alkyl carbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 3alkyl carbon atoms, or N-mono-substituted or N,N-disubstitutedaminoalkyl of 2 to 3 alkyl carbon atoms wherein said substituents arealkyl of 1 to 3 carbon atoms; and R²¹ represents hydrogen or methyl; orthe radical of formula —NR²⁰R²¹ represents pyrrolidinyl, piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl orthiamorpholinyl; and R²² represents alkyl radical of 1 to 3 carbonatoms; and R¹² and R¹³ each independently represent hydrogen, alkyl of1-5 carbon atoms, phenylalkyl of 1-3 alkyl carbon atoms, 5 to 6 ringmember heteroaralkyl of 1-3 alkyl carbon atoms, cycloalkyl of 3-6 ringmembers, cycloalkylmethyl of 3-6 ring members, hydroxyalkyl of 1-3carbon atoms, methoxyalkyl of 1-3 alkyl carbon atoms or phenyl. 3.Compound of claim 2, or a pharmaceutically acceptable salt, or esterthereof, wherein R¹ represents iso-propyl, sec-butyl, tert-butyl,3-propynyl, cyanomethyl, imidazolylmethyl, —CH₂CONH₂, —CH₂SCH₃,—CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃, or —C(CH₃)₂S(O)₂CH₃; R³ represents propyl, isoamyl, isobutyl, butyl, cyclohexyl,cycloheptyl, cyclopentylmethyl, or cyclohexylmethyl; R¹⁰ representshydrogen, methyl, ethyl, propyl, methoxymethyl, methoxyethyl,hydroxymethyl or hydroxyethyl; R¹¹ represents methyl, ethyl, propyl,isopropyl, butyl, secbutyl, isobutyl, tertbutyl, hydroxymethyl,hydroxyethyl, methoxymethyl or methoxyethyl; and, R⁴ represents phenyl,2-naphthyl, 4-methoxyphenyl, 4-hydroxphenyl, benzothiazol-5-yl,benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl,2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl,2,2-difluoro-1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or a radicalof the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl,2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl, 2-(1-piperazinyl)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(1-morpholinyl)ethyl,2-(1-thiamorpholinyl)ethyl or 2-(N,N-dimethylamino)ethyl; R²¹ representsa hydrogen; and R²² represents methyl; and R¹² and R¹³ eachindependently represent hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,benzyl, phenylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, furylmethyl,2-furylethyl, 2-hydroxyethyl, 2-methoxyethyl or phenyl.
 4. Compound ofclaim 3, or a pharmaceutically acceptable salt, or ester thereof; R¹represents sec-butyl, tert-butyl, isopropyl, 3-propynyl, cyanomethyl, or—C(CH₃)₂S(O)₂CH₃; R¹⁰ represents hydrogen, methyl, or ethyl; R¹¹represents methyl or ethyl; R⁴ represents phenyl, 4-methoxyphenyl,4-hydroxyphenyl, benzothiazol-5-yl, benzothiazol-6-yl,2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl,2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl,1,4-benzodioxanyl, 2-(methoxycarbonylamino)benzothiazol-6-yl or2-(methoxycarbonylamino)benzimidazol-5-yl; R¹² represents hydrogen ormethyl; and, R¹³ represents hydrogen, methyl, ethyl, propyl,cyclopropyl, isopropyl, benzyl, 2-phenylethyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl,2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, furylmethyl, 2-furylethyl or2-methoxyethyl.
 5. Compound of claim 1 wherein said pharmaceuticallyacceptable salt is hydrochloric acid salt, sulphuric acid salt,phosphoric acid salt, oxalic acid salt, maleic acid salt, succinic acidsalt, citric acid salt or methanesulfonic acid salt.
 6. Compound ofclaim 5 wherein said pharmaceutically acceptable salt is hydrochloricacid salt, oxalic acid salt, citric acid salt or methanesulfonic acidsalt.
 7. Composition comprising a compound of claim 1, or apharmaceutically acceptable salt or ester thereof and a pharmaceuticallyacceptable carrier.
 8. Method of inhibiting a retroviral proteasecomprising administering an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt or ester thereof.
 9. Method oftreating a retroviral infection comprising administering an effectiveamount of a composition of claim
 7. 10. Method of preventing replicationof a retrovirus comprising administering an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt or esterthereof.
 11. Method of preventing replication of a retrovirus in vitrocomprising administering an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt or ester thereof.
 12. Method oftreating AIDS comprising administering an effective amount of acomposition of claim
 7. 13. Compound of claim 1 represented by theformula:

wherein R¹, R³, R⁴, R¹⁰, R¹¹, R¹², and R¹³ are as defined in claim 1, ora pharmaceutically acceptable salt or ester thereof.
 14. Compound ofclaim 1 represented by the formula:

wherein R¹, R³, R⁴, R¹⁰, R¹¹, R¹², and R¹³ are as defined in claim 1, ora pharmaceutically acceptable salt or ester thereof.
 15. Compound ofclaim 1 represented by the formula:

wherein R¹, R³, R⁴, R¹⁰, R¹¹, R¹², and R¹³ are as defined in claim 1, ora pharmaceutically acceptable salt or ester thereof.
 16. Compoundrepresented by the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ representsalkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5carbon atoms, hydroxyalkyl of 1-3 carbon atoms, alkoxyalkyl of 1-3 alkyland 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3 alkyl carbon atoms,imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂S(O)₂NH₂, —CH₂SCH₃,—CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃ or—C(CH₃)₂S(O)₂CH₃; R³ represents alkyl of 1-5 carbon atoms, cycloalkyl of5-8 ring members or cycloalkylmethyl of 3-6 ring members; R¹⁰ representshydrogen, alkyl, hydroxyalkyl or alkoxyalkyl, wherein alkyl and alkoxyare each 1-3 carbon atoms; R¹¹ represents alkyl of 1-5 carbon atoms,hydroxyalkyl of 1-4 carbon atoms, alkoxyalkyl of 1-4 alkyl carbon atoms,benzyl, imidazolylmethyl, —CH₂CH₂CONH₂, —CH₂CONH₂, —CH₂CH₂SCH₃ or—CH₂SCH₃ or sulfone or sulfoxide derivatives thereof; R⁴ represents arylbenzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ringmember heterocyclo; or a radical of the formula

 wherein A and B each independently represent O, S, SO or SO₂; R⁶represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro; R⁷represents hydrogen, deuterium, methyl, fluoro or chloro; or a radicalof the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5carbon atoms, alkynyl of 2 to 5 carbon atoms, aralkyl of 1 to 5 alkylcarbon atoms, heteroaralkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, aminoalkyl of 2 to 5 carbon atoms, N-mono-substituted orN,N-disubstituted aminoalkyl of 2 to 5 alkyl carbon atoms wherein saidsubstituents are alkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkylcarbon atoms radicals, carboxyalkyl of 1 to 5 carbon atoms,alkoxycarbonylalkyl of 1 to 5 alkyl carbon atoms, cyanoalkyl of 1 to 5carbon atoms or hydroxyalkyl of 2 to 5 carbon atoms; R²¹ representshydrogen or alkyl of 1 to 3 carbon atoms; or the radical of formula—NR²⁰R²¹ represents a 5 to 6 ring member heterocyclo; and R²² representsalkyl of 1 to 3 carbon atoms or R²⁰R²¹N-alkyl radical of 1 to 3 alkylcarbon atoms; and R¹² and R¹³ each independently represent hydrogen,alkyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,hydroxyalkyl, alkoxyalkyl, aryl or heteroaryl, wherein alkyl is 1-5carbon atoms, cycloalkyl is 3-6 ring membered cycloalkyl optionallybenzo fused, and heteroaryl is 5 to 6 ring membered heteroaryloptionally benzo fused.
 17. Compound of claim 16, or a pharmaceuticallyacceptable salt thereof, wherein R¹ represents alkyl of 1-4 carbonatoms, alkenyl of 2-3 carbon atoms, alkynyl of 3-4 carbon atoms,cyanomethyl, imidazolylmethyl, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂S(O)₂NH₂,—CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃, —C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃ or—C(CH₃)₂S(O)₂CH₃; R³ represents alkyl of 1-5 carbon atoms,cycloalkylmethyl of 3-6 ring members, cyclohexyl, or cycloheptyl; and,R⁴ represents phenyl, 2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl,3,4-dimethoxyphenyl, 3-aminophenyl, 4-aminophenyl,2-amino-benzothiazol-5-yl, 2-amino-benzothiazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or aradical of the formula

 wherein A and B each represent O; R⁶ represents deuterium, methyl,ethyl, propyl, isopropyl or fluoro; and R⁷ represents hydrogen,deuterium, methyl or fluoro; or a radical of the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, alkyl of 1 to 5 carbon atoms, phenylalkyl of 1 to 3alkyl carbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 3alkyl carbon atoms, or N-mono-substituted or N,N-disubstitutedaminoalkyl of 2 to 3 alkyl carbon atoms wherein said substituents arealkyl of 1 to 3 carbon atoms; and R²¹ represents hydrogen or methyl; orthe radical of formula —NR²⁰R²¹ represents pyrrolidinyl, piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl orthiamorpholinyl; and R²² represents alkyl of 1 to 3 carbon atoms; andR¹² and R¹³ each independently represent hydrogen, alkyl of 1-5 carbonatoms, phenylalkyl of 1-3 alkyl carbon atoms, 5 to 6 ring memberheteroaralkyl of 1-3 alkyl carbon atoms, cycloalkyl of 3-6 ring members,cycloalkylmethyl of 3-6 ring members, hydroxyalkyl of 1-3 carbon atoms,methoxyalkyl of 1-3 alkyl carbon atoms or phenyl.
 18. Compound of claim17, or a pharmaceutically acceptable salt thereof, wherein R¹ representsiso-propyl, sec-butyl, tert-butyl, 3-propynyl, cyanomethyl,imidazolylmethyl, —CH₂CONH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂S(O)₂CH₃,—C(CH₃)₂SCH₃, —C(CH₃)₂S(O)CH₃, or —C(CH₃)₂S(O)₂CH₃; R³ representspropyl, isoamyl, isobutyl, butyl, cyclohexyl, cycloheptyl,cyclopentylmethyl, or cyclohexylmethyl; R¹⁰ represents hydrogen, methyl,ethyl, propyl, methoxymethyl, methoxyethyl, hydroxymethyl orhydroxyethyl; R¹¹ represents methyl, ethyl, propyl, isopropyl, butyl,secbutyl, isobutyl, tertbutyl, hydroxymethyl, hydroxyethyl,methoxymethyl or methoxyethyl; and, R⁴ represents phenyl, 2-naphthyl,4-methoxyphenyl, 4-hydroxphenyl, benzothiazol-5-yl, benzothiazol-6-yl,benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl,1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl,2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl,2,2-difluoro-1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or a radicalof the formula

 wherein Z represents O, S or NH; and R⁹ represents a radical of formula

 wherein Y represents O, S or NH; X represents a bond, O or NR²¹; R²⁰represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl,2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl, 2-(1-piperazinyl)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(1-morpholinyl)ethyl,2-(1-thiamorpholinyl)ethyl or 2-(N,N-dimethylamino)ethyl; R²¹ representsa hydrogen; and R²² represents methyl; and R¹² and R¹³ eachindependently represent hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,benzyl, phenylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, furylmethyl,2-furylethyl, 2-hydroxyethyl, 2-methoxyethyl or phenyl.
 19. Compound ofclaim 18, or a pharmaceutically acceptable salt thereof; R¹ representssec-butyl, tert-butyl, iso-propyl, 3-propynyl, cyanomethyl, or—C(CH₃)₂S(O)₂CH₃; R¹⁰ represents hydrogen, methyl, or ethyl; R¹¹represents methyl, or ethyl; R⁴ represents phenyl, 4-methoxyphenyl,4-hydroxyphenyl, benzothiazol-5-yl, benzothiazol-6-yl,2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl,2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2-(methoxycarbonylamino)benzothiazol-6-yl or2-(methoxycarbonylamino)benzimidazol-5-yl; R¹² represents hydrogen ormethyl; and, R¹³ represents hydrogen, methyl, ethyl, propyl,cyclopropyl, isopropyl, benzyl, 2-phenylethyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl,2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, furylmethyl, 2-furylethyl or2-methoxyethyl.
 20. Compound of claim 16 wherein said pharmaceuticallyacceptable salt is hydrochloric acid salt, sulphuric acid salt,phosphoric acid salt, oxalic acid salt, maleic acid salt, succinic acidsalt, citric acid salt or methanesulfonic acid salt.